Melanoma

Melanomas have been designated as small melanomas or micromelanomas according to their long-axis diameter (<6 mm and ≤3 mm, respectively).^1-3 Because small-diameter melanomas also have the potential to metastasize, particularly if nodular, early diagnosis can be highly rewarding. Deep melanomas with small diameters may have the same potential for metastasis as large-diameter melanomas. In this context, dermoscopy, digital dermoscopic monitoring, and total-body photography are useful in clinical practice. However, these techniques are of limited utility for small, dermoscopic feature–poor melanomas. Conversely, less than 10% of changing lesions, which are spotted via digital dermoscopic surveillance, turn out to be melanomas; therefore, simply removing all changing lesions may result in many unnecessary excisions of benign lesions.⁴

In vivo reflectance confocal microscopy (RCM) is an advanced technique that allows recognition of the architectural and cellular details of pigmented lesions. Reflectance confocal microscopy has the potential to reduce the rate of unnecessary excisions and to diminish the risk for missing a melanoma.^5-7 In meta-analyses, RCM sensitivity was reported as 90% to 93% and specificity was reported as 78% to 82% in detecting melanoma.^8,9

We describe a case that highlights the potential role of RCM in the diagnosis of small-diameter melanomas.

Case Report

A 57-year-old man with Fitzpatrick skin type III presented to the dermato-oncology unit for evaluation of multiple nevi. He was otherwise healthy and denied a history of skin cancer. Total-body skin examination with dermoscopy was performed, and several mildly atypical lesions were identified. We decided to perform digital dermoscopic monitoring. The patient’s 6-month monitoring appointment had been scheduled, but he did not arrive for the follow-up visit until 10 months after the initial examination. A lesion on the left arm, which initially was 1.5 mm in diameter, had enlarged. It was now a dark brown–gray papule with a 2.5-mm diameter (Figure 1). Dermoscopy revealed grayish globules/dots at the center of the lesion, reticular gray-blue areas, and few milialike cysts; at the periphery, a narrow rim of brownish delicate pigment network also was seen (Figure 2). The clinical and dermoscopic differential diagnosis was either an atypical nevus or an early melanoma. For a more precise diagnosis before excision, the lesion was evaluated with RCM, which takes 10 to 15 minutes to perform.

Under RCM at the epidermis level, there was a cobblestone pattern that showed a focus with mild disarrangement and few small, roundish, nucleated cells (Figure 3). A mosaic image, akin to low-magnification microscopy that enables overview of the entire lesion, at the level of the dermoepidermal junction (DEJ) showed an overall irregular meshwork pattern. Higher-magnification optical sections showed marked and diffuse (extending >10% of lesion area) architectural disorder with confluent junctional nests that were irregular to bizarre in shape and uneven in size and spacing as well as edged and nonedged papillae. At the superficial dermal level, atypical bright nucleated cells (>5 cells/mm²) were observed (Figure 4). Bright dots and/or plump bright cells within papillae also were observed. These RCM findings were highly suggestive for melanoma.

Histopathology showed an asymmetric, junctional, lentiginous, and nested proliferation of atypical epithelioid melanocytes, with few melanocytes in a pagetoid spread. There were small nests of atypical epithelioid melanocytes at the superficial dermis extending to a depth of 0.3 mm. The atypical epithelioid melanocytes displayed angulated hyperchromatic nuclei with conspicuous nucleoli and dusty brown cytoplasm. There was notable inflammation and pigment incontinence at the dermis. There was no evidence of ulceration or mitosis at the dermal component. The diagnosis of a pT1a malignant melanoma was reported (Figure 5).

Comment

A small but enlarging dark gray papule with reticular gray-blue areas under dermoscopy in a 57-year-old man is obviously suspicious for melanoma. In daily practice, this type of small-diameter melanoma is difficult to diagnose with high confidence. We balance our aim to diagnose melanomas early with the need to reduce unnecessary excisions. Reflectance confocal microscopy may allow the clinician to arrive at the correct diagnosis and management decision with confidence before excision of the lesion.

The distinction of a small-diameter melanoma from a nevus via RCM relies on evaluation of the architectural and cellular features. Findings on RCM in small-diameter melanomas have been scarcely reported in the literature; Pupelli et al¹⁰ evaluated small melanomas with a diameter of 2 to 5 mm. Among these small-diameter melanomas, the RCM features suggestive for melanomas were the presence of cytologic atypia with cellular pleomorphism, architectural disorder with irregular nests, at least 5 pagetoid cells/mm², dendrites or tangled lines (ie, short fine lines with no visible nucleus interlacing with the adjacent keratinocytes) within the epidermis, and atypical roundish cells at the DEJ.¹⁰

The distinction between an atypical nevus and a small-diameter melanoma using RCM occasionally may be challenging.¹¹ Pellacani et al¹² reported an algorithm to distinguish melanoma from atypical nevi. According to this algorithm, when at least 1 of the architectural atypia features (irregular junctional nests, short interconnections between junctional nests, and nonhomogeneous cellularity within junctional nests) and at least 1 of the cytologic atypia features (round pagetoid cells or atypical cells at the DEJ) are observed simultaneously, the lesion is diagnosed as a dysplastic nevus or a melanoma in the first step. In the second step, the RCM diagnosis of melanoma requires at least 1 of 3 parameters: roundish pagetoid cells encompassing at least 50% of the lesional area at the spinous layer, atypical cells involving at least 50% of the lesional area at the DEJ level, and nonedged papillae involving at least 10% of the lesional area.¹² Accordingly, our case corresponded with these RCM criteria for a melanoma, given that there were irregular junctional nests, atypical cells at the DEJ, and nonedged papillae involving at least 10% of the lesion.

The current limitations of RCM are the high cost of the device (approximately $58,125–$139,400 for different models), the amount of time needed to train staff in RCM units (seminars, congresses, and special courses organized by the International Confocal Working Group), and the amount of time needed for evaluation of individual lesions (15–20 minutes). However, RCM can be valuable in the clinical diagnosis of difficult lesions, as seen in our case.

Conclusion

Our case highlights the benefit of RCM in allowing the confident diagnosis and correct management of a small-diameter melanoma that turned out to be a melanoma with 0.3-mm Breslow thickness. Even so, histopathologic evaluation remains the gold standard for the diagnosis of melanoma.

Melanomas have been designated as small melanomas or micromelanomas according to their long-axis diameter (<6 mm and ≤3 mm, respectively).^1-3 Because small-diameter melanomas also have the potential to metastasize, particularly if nodular, early diagnosis can be highly rewarding. Deep melanomas with small diameters may have the same potential for metastasis as large-diameter melanomas. In this context, dermoscopy, digital dermoscopic monitoring, and total-body photography are useful in clinical practice. However, these techniques are of limited utility for small, dermoscopic feature–poor melanomas. Conversely, less than 10% of changing lesions, which are spotted via digital dermoscopic surveillance, turn out to be melanomas; therefore, simply removing all changing lesions may result in many unnecessary excisions of benign lesions.⁴

In vivo reflectance confocal microscopy (RCM) is an advanced technique that allows recognition of the architectural and cellular details of pigmented lesions. Reflectance confocal microscopy has the potential to reduce the rate of unnecessary excisions and to diminish the risk for missing a melanoma.^5-7 In meta-analyses, RCM sensitivity was reported as 90% to 93% and specificity was reported as 78% to 82% in detecting melanoma.^8,9

We describe a case that highlights the potential role of RCM in the diagnosis of small-diameter melanomas.

Case Report

A 57-year-old man with Fitzpatrick skin type III presented to the dermato-oncology unit for evaluation of multiple nevi. He was otherwise healthy and denied a history of skin cancer. Total-body skin examination with dermoscopy was performed, and several mildly atypical lesions were identified. We decided to perform digital dermoscopic monitoring. The patient’s 6-month monitoring appointment had been scheduled, but he did not arrive for the follow-up visit until 10 months after the initial examination. A lesion on the left arm, which initially was 1.5 mm in diameter, had enlarged. It was now a dark brown–gray papule with a 2.5-mm diameter (Figure 1). Dermoscopy revealed grayish globules/dots at the center of the lesion, reticular gray-blue areas, and few milialike cysts; at the periphery, a narrow rim of brownish delicate pigment network also was seen (Figure 2). The clinical and dermoscopic differential diagnosis was either an atypical nevus or an early melanoma. For a more precise diagnosis before excision, the lesion was evaluated with RCM, which takes 10 to 15 minutes to perform.

Under RCM at the epidermis level, there was a cobblestone pattern that showed a focus with mild disarrangement and few small, roundish, nucleated cells (Figure 3). A mosaic image, akin to low-magnification microscopy that enables overview of the entire lesion, at the level of the dermoepidermal junction (DEJ) showed an overall irregular meshwork pattern. Higher-magnification optical sections showed marked and diffuse (extending >10% of lesion area) architectural disorder with confluent junctional nests that were irregular to bizarre in shape and uneven in size and spacing as well as edged and nonedged papillae. At the superficial dermal level, atypical bright nucleated cells (>5 cells/mm²) were observed (Figure 4). Bright dots and/or plump bright cells within papillae also were observed. These RCM findings were highly suggestive for melanoma.

Histopathology showed an asymmetric, junctional, lentiginous, and nested proliferation of atypical epithelioid melanocytes, with few melanocytes in a pagetoid spread. There were small nests of atypical epithelioid melanocytes at the superficial dermis extending to a depth of 0.3 mm. The atypical epithelioid melanocytes displayed angulated hyperchromatic nuclei with conspicuous nucleoli and dusty brown cytoplasm. There was notable inflammation and pigment incontinence at the dermis. There was no evidence of ulceration or mitosis at the dermal component. The diagnosis of a pT1a malignant melanoma was reported (Figure 5).

Comment

A small but enlarging dark gray papule with reticular gray-blue areas under dermoscopy in a 57-year-old man is obviously suspicious for melanoma. In daily practice, this type of small-diameter melanoma is difficult to diagnose with high confidence. We balance our aim to diagnose melanomas early with the need to reduce unnecessary excisions. Reflectance confocal microscopy may allow the clinician to arrive at the correct diagnosis and management decision with confidence before excision of the lesion.

The distinction of a small-diameter melanoma from a nevus via RCM relies on evaluation of the architectural and cellular features. Findings on RCM in small-diameter melanomas have been scarcely reported in the literature; Pupelli et al¹⁰ evaluated small melanomas with a diameter of 2 to 5 mm. Among these small-diameter melanomas, the RCM features suggestive for melanomas were the presence of cytologic atypia with cellular pleomorphism, architectural disorder with irregular nests, at least 5 pagetoid cells/mm², dendrites or tangled lines (ie, short fine lines with no visible nucleus interlacing with the adjacent keratinocytes) within the epidermis, and atypical roundish cells at the DEJ.¹⁰

The distinction between an atypical nevus and a small-diameter melanoma using RCM occasionally may be challenging.¹¹ Pellacani et al¹² reported an algorithm to distinguish melanoma from atypical nevi. According to this algorithm, when at least 1 of the architectural atypia features (irregular junctional nests, short interconnections between junctional nests, and nonhomogeneous cellularity within junctional nests) and at least 1 of the cytologic atypia features (round pagetoid cells or atypical cells at the DEJ) are observed simultaneously, the lesion is diagnosed as a dysplastic nevus or a melanoma in the first step. In the second step, the RCM diagnosis of melanoma requires at least 1 of 3 parameters: roundish pagetoid cells encompassing at least 50% of the lesional area at the spinous layer, atypical cells involving at least 50% of the lesional area at the DEJ level, and nonedged papillae involving at least 10% of the lesional area.¹² Accordingly, our case corresponded with these RCM criteria for a melanoma, given that there were irregular junctional nests, atypical cells at the DEJ, and nonedged papillae involving at least 10% of the lesion.

The current limitations of RCM are the high cost of the device (approximately $58,125–$139,400 for different models), the amount of time needed to train staff in RCM units (seminars, congresses, and special courses organized by the International Confocal Working Group), and the amount of time needed for evaluation of individual lesions (15–20 minutes). However, RCM can be valuable in the clinical diagnosis of difficult lesions, as seen in our case.

Conclusion

Our case highlights the benefit of RCM in allowing the confident diagnosis and correct management of a small-diameter melanoma that turned out to be a melanoma with 0.3-mm Breslow thickness. Even so, histopathologic evaluation remains the gold standard for the diagnosis of melanoma.

Melanomas have been designated as small melanomas or micromelanomas according to their long-axis diameter (<6 mm and ≤3 mm, respectively).^1-3 Because small-diameter melanomas also have the potential to metastasize, particularly if nodular, early diagnosis can be highly rewarding. Deep melanomas with small diameters may have the same potential for metastasis as large-diameter melanomas. In this context, dermoscopy, digital dermoscopic monitoring, and total-body photography are useful in clinical practice. However, these techniques are of limited utility for small, dermoscopic feature–poor melanomas. Conversely, less than 10% of changing lesions, which are spotted via digital dermoscopic surveillance, turn out to be melanomas; therefore, simply removing all changing lesions may result in many unnecessary excisions of benign lesions.⁴

In vivo reflectance confocal microscopy (RCM) is an advanced technique that allows recognition of the architectural and cellular details of pigmented lesions. Reflectance confocal microscopy has the potential to reduce the rate of unnecessary excisions and to diminish the risk for missing a melanoma.^5-7 In meta-analyses, RCM sensitivity was reported as 90% to 93% and specificity was reported as 78% to 82% in detecting melanoma.^8,9

We describe a case that highlights the potential role of RCM in the diagnosis of small-diameter melanomas.

Case Report

A 57-year-old man with Fitzpatrick skin type III presented to the dermato-oncology unit for evaluation of multiple nevi. He was otherwise healthy and denied a history of skin cancer. Total-body skin examination with dermoscopy was performed, and several mildly atypical lesions were identified. We decided to perform digital dermoscopic monitoring. The patient’s 6-month monitoring appointment had been scheduled, but he did not arrive for the follow-up visit until 10 months after the initial examination. A lesion on the left arm, which initially was 1.5 mm in diameter, had enlarged. It was now a dark brown–gray papule with a 2.5-mm diameter (Figure 1). Dermoscopy revealed grayish globules/dots at the center of the lesion, reticular gray-blue areas, and few milialike cysts; at the periphery, a narrow rim of brownish delicate pigment network also was seen (Figure 2). The clinical and dermoscopic differential diagnosis was either an atypical nevus or an early melanoma. For a more precise diagnosis before excision, the lesion was evaluated with RCM, which takes 10 to 15 minutes to perform.

Under RCM at the epidermis level, there was a cobblestone pattern that showed a focus with mild disarrangement and few small, roundish, nucleated cells (Figure 3). A mosaic image, akin to low-magnification microscopy that enables overview of the entire lesion, at the level of the dermoepidermal junction (DEJ) showed an overall irregular meshwork pattern. Higher-magnification optical sections showed marked and diffuse (extending >10% of lesion area) architectural disorder with confluent junctional nests that were irregular to bizarre in shape and uneven in size and spacing as well as edged and nonedged papillae. At the superficial dermal level, atypical bright nucleated cells (>5 cells/mm²) were observed (Figure 4). Bright dots and/or plump bright cells within papillae also were observed. These RCM findings were highly suggestive for melanoma.

Histopathology showed an asymmetric, junctional, lentiginous, and nested proliferation of atypical epithelioid melanocytes, with few melanocytes in a pagetoid spread. There were small nests of atypical epithelioid melanocytes at the superficial dermis extending to a depth of 0.3 mm. The atypical epithelioid melanocytes displayed angulated hyperchromatic nuclei with conspicuous nucleoli and dusty brown cytoplasm. There was notable inflammation and pigment incontinence at the dermis. There was no evidence of ulceration or mitosis at the dermal component. The diagnosis of a pT1a malignant melanoma was reported (Figure 5).

Comment

A small but enlarging dark gray papule with reticular gray-blue areas under dermoscopy in a 57-year-old man is obviously suspicious for melanoma. In daily practice, this type of small-diameter melanoma is difficult to diagnose with high confidence. We balance our aim to diagnose melanomas early with the need to reduce unnecessary excisions. Reflectance confocal microscopy may allow the clinician to arrive at the correct diagnosis and management decision with confidence before excision of the lesion.

The distinction of a small-diameter melanoma from a nevus via RCM relies on evaluation of the architectural and cellular features. Findings on RCM in small-diameter melanomas have been scarcely reported in the literature; Pupelli et al¹⁰ evaluated small melanomas with a diameter of 2 to 5 mm. Among these small-diameter melanomas, the RCM features suggestive for melanomas were the presence of cytologic atypia with cellular pleomorphism, architectural disorder with irregular nests, at least 5 pagetoid cells/mm², dendrites or tangled lines (ie, short fine lines with no visible nucleus interlacing with the adjacent keratinocytes) within the epidermis, and atypical roundish cells at the DEJ.¹⁰

The distinction between an atypical nevus and a small-diameter melanoma using RCM occasionally may be challenging.¹¹ Pellacani et al¹² reported an algorithm to distinguish melanoma from atypical nevi. According to this algorithm, when at least 1 of the architectural atypia features (irregular junctional nests, short interconnections between junctional nests, and nonhomogeneous cellularity within junctional nests) and at least 1 of the cytologic atypia features (round pagetoid cells or atypical cells at the DEJ) are observed simultaneously, the lesion is diagnosed as a dysplastic nevus or a melanoma in the first step. In the second step, the RCM diagnosis of melanoma requires at least 1 of 3 parameters: roundish pagetoid cells encompassing at least 50% of the lesional area at the spinous layer, atypical cells involving at least 50% of the lesional area at the DEJ level, and nonedged papillae involving at least 10% of the lesional area.¹² Accordingly, our case corresponded with these RCM criteria for a melanoma, given that there were irregular junctional nests, atypical cells at the DEJ, and nonedged papillae involving at least 10% of the lesion.

The current limitations of RCM are the high cost of the device (approximately $58,125–$139,400 for different models), the amount of time needed to train staff in RCM units (seminars, congresses, and special courses organized by the International Confocal Working Group), and the amount of time needed for evaluation of individual lesions (15–20 minutes). However, RCM can be valuable in the clinical diagnosis of difficult lesions, as seen in our case.

Conclusion

Our case highlights the benefit of RCM in allowing the confident diagnosis and correct management of a small-diameter melanoma that turned out to be a melanoma with 0.3-mm Breslow thickness. Even so, histopathologic evaluation remains the gold standard for the diagnosis of melanoma.

Practice Gap

An essential part of training for a micrographic surgery and dermatologic oncology fellowship and scope of practice involves planning and execution of reconstructive surgery for Mohs defects. Recently, a surgical pearl presented by Rickstrew and colleagues¹ highlighted the use of different colored surgical marking pens and their benefit in a trainee-based environment.

Delineating multiple options for reconstruction with different colored markers on live patients allows fellows in-training to participate in surgical planning but introduces more markings or drawings that need to be wiped off during or after surgery, potentially prolonging operative time. Furthermore, the Rickstrew approach has the potential to (1) cause unnecessary emotional distress for the patient during surgical planning and (2) add to the cost of surgery with the purchase of various colors of surgical markers.

Technique

To improve patient experience and trainee education, we propose fine-tuning the colored marker approach by utilizing a digital drawing program for surgical planning prior to the procedure. We recommend Snip & Sketch—a free, readily accessible digital annotating application that runs on the Microsoft Windows 10 operating system (https://www.microsoft.com/en-us/p/snip-sketch/9mz95kl8mr0l#activetab=pivot:overviewtab)—to mark up screenshot photographs of postoperative Mohs defects from the electronic medical record.

Using Snip & Sketch, the fellow in-training can then use, for example, a green “digital pen” to draw on the captured image and plan their surgical repairs (Figure 1) without input from the attending physician. Different colored pens can be used to highlight nerves, vessels, relaxed skin tension lines, and tension vectors associated with flap movement.

Subsequently, the attending physician, using a different color digital pen—say, blue—can design alternative reconstructive options (Figure 1). Suture lines also can be drawn to outline the predicted appearance of surgical scars (Figure 2).

Then, the attending physician and fellow in-training brainstorm and discuss the advantages and disadvantages of each reconstructive option to determine the optimal approach to repairing the Mohs defect.

Advantages and Disadvantages

The main advantage of using a digital drawing program is that it is time-saving and cost-efficient. Digital planning also spares the patient undue anxiety from listening to the discussion on each repair option.

The primary downside of digital surgical planning is that it is 2-dimensional, thus providing an incomplete representation of a 3-dimensional cutaneous structure. In addition, skin laxity, flap mobility, and free-margin distortion cannot be fully appreciated on a 2-dimensional image.

Despite these drawbacks, digital surgical planning provides trainees with an active learning experience through a more collaborative and comprehensive discussion of reconstructive options.

Practice Implications

Active learning using an electronic device has been validated as a beneficial addition to Mohs micrographic surgery training.² Utilizing a digitized annotating program for surgical planning increases the independence of trainees and allows immediate feedback from the attending physician. The synergy of digital technology and collaborative learning helps cultivate the next generation of confident and competent Mohs surgeons.

Practice Gap

An essential part of training for a micrographic surgery and dermatologic oncology fellowship and scope of practice involves planning and execution of reconstructive surgery for Mohs defects. Recently, a surgical pearl presented by Rickstrew and colleagues¹ highlighted the use of different colored surgical marking pens and their benefit in a trainee-based environment.

Delineating multiple options for reconstruction with different colored markers on live patients allows fellows in-training to participate in surgical planning but introduces more markings or drawings that need to be wiped off during or after surgery, potentially prolonging operative time. Furthermore, the Rickstrew approach has the potential to (1) cause unnecessary emotional distress for the patient during surgical planning and (2) add to the cost of surgery with the purchase of various colors of surgical markers.

Technique

To improve patient experience and trainee education, we propose fine-tuning the colored marker approach by utilizing a digital drawing program for surgical planning prior to the procedure. We recommend Snip & Sketch—a free, readily accessible digital annotating application that runs on the Microsoft Windows 10 operating system (https://www.microsoft.com/en-us/p/snip-sketch/9mz95kl8mr0l#activetab=pivot:overviewtab)—to mark up screenshot photographs of postoperative Mohs defects from the electronic medical record.

Using Snip & Sketch, the fellow in-training can then use, for example, a green “digital pen” to draw on the captured image and plan their surgical repairs (Figure 1) without input from the attending physician. Different colored pens can be used to highlight nerves, vessels, relaxed skin tension lines, and tension vectors associated with flap movement.

Subsequently, the attending physician, using a different color digital pen—say, blue—can design alternative reconstructive options (Figure 1). Suture lines also can be drawn to outline the predicted appearance of surgical scars (Figure 2).

Then, the attending physician and fellow in-training brainstorm and discuss the advantages and disadvantages of each reconstructive option to determine the optimal approach to repairing the Mohs defect.

Advantages and Disadvantages

The main advantage of using a digital drawing program is that it is time-saving and cost-efficient. Digital planning also spares the patient undue anxiety from listening to the discussion on each repair option.

The primary downside of digital surgical planning is that it is 2-dimensional, thus providing an incomplete representation of a 3-dimensional cutaneous structure. In addition, skin laxity, flap mobility, and free-margin distortion cannot be fully appreciated on a 2-dimensional image.

Despite these drawbacks, digital surgical planning provides trainees with an active learning experience through a more collaborative and comprehensive discussion of reconstructive options.

Practice Implications

Active learning using an electronic device has been validated as a beneficial addition to Mohs micrographic surgery training.² Utilizing a digitized annotating program for surgical planning increases the independence of trainees and allows immediate feedback from the attending physician. The synergy of digital technology and collaborative learning helps cultivate the next generation of confident and competent Mohs surgeons.

Practice Gap

An essential part of training for a micrographic surgery and dermatologic oncology fellowship and scope of practice involves planning and execution of reconstructive surgery for Mohs defects. Recently, a surgical pearl presented by Rickstrew and colleagues¹ highlighted the use of different colored surgical marking pens and their benefit in a trainee-based environment.

Delineating multiple options for reconstruction with different colored markers on live patients allows fellows in-training to participate in surgical planning but introduces more markings or drawings that need to be wiped off during or after surgery, potentially prolonging operative time. Furthermore, the Rickstrew approach has the potential to (1) cause unnecessary emotional distress for the patient during surgical planning and (2) add to the cost of surgery with the purchase of various colors of surgical markers.

Technique

To improve patient experience and trainee education, we propose fine-tuning the colored marker approach by utilizing a digital drawing program for surgical planning prior to the procedure. We recommend Snip & Sketch—a free, readily accessible digital annotating application that runs on the Microsoft Windows 10 operating system (https://www.microsoft.com/en-us/p/snip-sketch/9mz95kl8mr0l#activetab=pivot:overviewtab)—to mark up screenshot photographs of postoperative Mohs defects from the electronic medical record.

Using Snip & Sketch, the fellow in-training can then use, for example, a green “digital pen” to draw on the captured image and plan their surgical repairs (Figure 1) without input from the attending physician. Different colored pens can be used to highlight nerves, vessels, relaxed skin tension lines, and tension vectors associated with flap movement.

Subsequently, the attending physician, using a different color digital pen—say, blue—can design alternative reconstructive options (Figure 1). Suture lines also can be drawn to outline the predicted appearance of surgical scars (Figure 2).

Then, the attending physician and fellow in-training brainstorm and discuss the advantages and disadvantages of each reconstructive option to determine the optimal approach to repairing the Mohs defect.

Advantages and Disadvantages

The main advantage of using a digital drawing program is that it is time-saving and cost-efficient. Digital planning also spares the patient undue anxiety from listening to the discussion on each repair option.

The primary downside of digital surgical planning is that it is 2-dimensional, thus providing an incomplete representation of a 3-dimensional cutaneous structure. In addition, skin laxity, flap mobility, and free-margin distortion cannot be fully appreciated on a 2-dimensional image.

Despite these drawbacks, digital surgical planning provides trainees with an active learning experience through a more collaborative and comprehensive discussion of reconstructive options.

Practice Implications

Active learning using an electronic device has been validated as a beneficial addition to Mohs micrographic surgery training.² Utilizing a digitized annotating program for surgical planning increases the independence of trainees and allows immediate feedback from the attending physician. The synergy of digital technology and collaborative learning helps cultivate the next generation of confident and competent Mohs surgeons.

Anyone who practices Mohs micrographic surgery is likely to know the name Hugh Greenway, MD, the longtime head of Mohs and dermatologic surgery at Scripps Clinic in San Diego, who was also recently selected as program director for cutaneous oncology at Scripps MD Anderson Cancer Center in San Diego. He is also a former president of the American College of Mohs Surgery.

After earning his medical degree from the Medical College of Georgia, Augusta, in 1974, Dr. Greenway was fellowship trained in Mohs skin cancer surgery by Frederic E. Mohs, MD, at the University of Wisconsin–Madison. He completed his dermatology residency at the Naval Medical Center San Diego and joined Scripps Clinic in 1983, where he launched the institution’s first Mohs surgery program, as well as a popular annual intensive course in superficial anatomy and cutaneous surgery that bears his name. He was also the first physician in the world to use interferon as a nonsurgical treatment of basal cell carcinoma.

Courtesy Scripps Clinic

To date, Dr. Greenway has performed more than 41,000 Mohs surgery cases and has trained 61 fellows who practice in academic and clinical settings. In 2017, he received the Frederic E. Mohs Award from the ACMS at the college’s annual meeting. He is also a past CEO of Scripps Clinic. In this Q&A, Dr. Greenway opens up about what it was like to train with Dr. Mohs, what makes a good Mohs surgeon, and why he’s excited about the future of dermatology.
 

I understand that you first became interested in a medical career after meeting Dr. Carl Jones, a friend of your father who was your Scoutmaster in the Boy Scouts in Georgia. What about Dr. Jones inspired you to pursue a career in medicine?

Dr. Jones was an internist/allergist in Atlanta, where I grew up. His three sons and I were friends. My dad had dealt with several medical problems being injured in World War II and subsequently undergoing a couple of kidney transplantations, so I developed an interest in medicine personally. Even though Dr. Jones was a specialist, he started out as a family doctor like I did, so he was interested in the whole person and all of his or her medical problems as opposed to those related to his specialty only. I traveled with the Boy Scouts to camp at places like Valley Forge in Pennsylvania, and Dr. Jones was involved with the medical set-ups of those large events. That also contributed to my interest in medicine.

As part of your 9-year service in the U.S. Navy, you spent 2 years as the flight surgeon at NAS Atlanta/Dobbins Air Force Base. What was your most memorable experience from that assignment?

Dobbins is a large facility with two Lockheed plants, and the Air Force had built the medical clinic, which was staffed by the Navy. Getting to know some of the active-duty members of the Air Force, the Navy, and the National Guard, and their commitment to our country, was memorable. Jimmy Carter was the president in those days. When he would fly in Dobbins, one of my jobs as the flight surgeon was to be on base when Air Force One landed or departed. One night, we had a DC-9 commercial aircraft coming from Huntsville, Ala., to Atlanta that got caught in a thunderstorm a little above 30,000 feet. Both engines went out and the aircraft essentially became a glider. The pilots tried to land on our runway but unfortunately, they ended up 4 miles short. We were heavily involved in responding to the crash, which was a tragic event. I also learned to fly (second seat) different types of aircraft during my assignment at NAS Atlanta/Dobbins Air Force Base, everything from the large C-5s to Navy fighter jets and helicopters. Coincidentally, Dr. Jones was involved with a couple of free health clinics in Atlanta when I was stationed there. Every Tuesday night, my wife (who is a nurse) and I would volunteer at a clinic in Cabbagetown, which was one of the poorer areas of Atlanta. It was a chance to give back to a group of people who didn’t have a whole lot.

In the middle your dermatology residency at Naval Medical Center San Diego, you were selected by Dr. Mohs for fellowship training in Mohs skin cancer surgery at the University of Wisconsin–Madison. What do you remember most about your training with Dr. Mohs?

Dr. Mohs was a kind, humble man who had this great idea about skin cancer. He was not a dermatologist; he was a general surgeon. The technique he developed was originally called chemosurgery because he put a chemical onto the skin. This was known as the fixed-tissue technique. Then we had a fresh-tissue technique, where we did not use the chemical, but we were able to use local anesthesia right away. That developed into the Mohs surgery we know today. Dr. Mohs did not name it that; he was very humble, but he was very proud of his technique. He was also a very hard worker. On the first day of my fellowship, I started at 7 in the morning and ended at 7 at night. It was the same for the last day of my fellowship. He also had an excellent office staff, many of whom had worked with him for many years. Patients with difficult skin cancers traveled to Madison from all over the world because there weren’t that many Mohs surgery clinics in those days. During the latter part of my fellowship, Michael McCall, MD, and I had the opportunity to remove a skin cancer from the nose of Dr. Mohs. We presented the case at a national conference, and I titled the talk “Mohs Surgery for Mohs’ Nose.”

Early in your career Dr. Mohs asked you to take over his practice, but you accepted an offer to establish the first Mohs surgery office at Scripps in San Diego instead. What convinced you to head West?

After my fellowship, I returned to San Diego to complete my residency with the Navy, where we opened a Mohs surgery clinic. Dr. Mohs came out for the ribbon cutting. During that time, I was taking care of several patients that he had treated in Wisconsin. Through that my wife and I ended up going to dinner with Cecil and Ida Green, philanthropists who made several financial gifts to Scripps Clinic – and for whom Scripps Green Hospital is named. Cecil cofounded Texas Instruments and was knighted by Queen Elizabeth. During dinner, he suggested that I stay in San Diego for a year and work at Scripps after my residency assignment with the Navy. I agreed and have been here ever since.

What do you find most interesting about Mohs surgery?

In Mohs surgery, you’re able to provide not only surgical care to eliminate the tumor, but also the pathology and the reconstruction. That was interesting to me. Dr. Mohs was not that interested in reconstruction. He was more focused on the tumor, in part because with the original fixed-tissue technique you could not do the reconstruction. You had to wait for an extra layer of tissue to separate. But with the fresh-tissue technique, you were able to provide the reconstruction that day. Mohs surgery deals with a subset of tumors that are challenging to treat. That also spiked my academic and clinical interest.

In your opinion, what’s been the most important advance in Mohs surgery to date?

In recent years, immunology has come into play, so now we have teams of clinicians in dermatology, medical oncology, surgery, and other subspecialties providing patients the best of care. In the arena of Mohs surgery itself, in the 1980s, the American College of Mohs Surgery developed a 1-year fellowship program, which enabled us to train many men and women to practice Mohs surgery. Most of them are dermatologists.

Please complete the sentence: “You can tell a good Mohs surgeon by the way he/she ...”

Treats patients, is willing to spend time with them, and shows an interest in them. One of the things we should strive for is to let patients know that they as a person are important; it’s not just the melanoma on their nose. We’re not only dealing with a skin cancer; we’re dealing with a patient who has skin cancer.

For the past 39 years, you have led Hugh Greenway’s Superficial Anatomy and Cutaneous Surgery course, which takes place every January in San Diego. What’s been key to sustaining this training course for nearly 4 decades?

There have been many people involved in its success, so it’s not just me. When I first started my practice, there really was not a focus on anatomy in the general dermatologic community. Dermatologic surgery textbooks contained very little content on surgical anatomy so I developed an interest a putting together a course that would cover some of this material. I met with Terence Davidson, MD, an otolaryngologist who was dean of continuing medical education at the University of California, San Diego. The course includes lectures from experts in many subspecialties and hands-on laboratories using cadavers to work on anatomy and surgical techniques. After about 16 years of doing the course Dr. Davidson told me: “When we started this course, as a group, the head and neck surgeons were the best to do the reconstructions on the face with skin flaps and grafts and layered closures. But now, as a group, the dermatologists are best at doing that.” That’s what we want to hear in medical education.

During the peak of the COVID-19 pandemic, what were your most significant challenges from both a clinical and a personal standpoint?

I’m fortunate to practice at a place like Scripps, where there are many resources to look at what was happening with COVID-19. Clinically, we had to put a lot of things on hold, but we tried our best to keep our cancer patients in particular in the forefront of care. It has been a challenge, but fortunately we have been able to take care of patients after a brief timeout. Many of us remember the polio vaccine back in the 1950s. Having worked overseas and at missionary hospital where we had children die of measles because they were not vaccinated gave me a larger appreciation for the importance of vaccines. I recommend all young physicians who work with me to read, “The Great Influenza: The Story of the Deadliest Pandemic in History,” by John M. Barry, which recounts the 1918 flu epidemic.

Who inspires you most in your work today?

I don’t view what I do as work. Dr. Jones and Dr. Mohs continue to inspire me with what they accomplished during their careers. You have to love people and love patients. Every patient who comes to see me has a story, so I try to understand their story. One of the things I really enjoy is training the young fellows. We train three Mohs fellows per year at Scripps, and it’s a great challenge every day.

What development in dermatology are you most excited about in the next 5 years?

Dermatology will continue to evolve just like all other medical specialties. We’re going to see a large growth in telemedicine, and immunotherapy is playing a key role in dermatologic oncology. What excites me the most in medicine is the young people who enter the field willing to contribute their lives to helping others.

Anyone who practices Mohs micrographic surgery is likely to know the name Hugh Greenway, MD, the longtime head of Mohs and dermatologic surgery at Scripps Clinic in San Diego, who was also recently selected as program director for cutaneous oncology at Scripps MD Anderson Cancer Center in San Diego. He is also a former president of the American College of Mohs Surgery.

After earning his medical degree from the Medical College of Georgia, Augusta, in 1974, Dr. Greenway was fellowship trained in Mohs skin cancer surgery by Frederic E. Mohs, MD, at the University of Wisconsin–Madison. He completed his dermatology residency at the Naval Medical Center San Diego and joined Scripps Clinic in 1983, where he launched the institution’s first Mohs surgery program, as well as a popular annual intensive course in superficial anatomy and cutaneous surgery that bears his name. He was also the first physician in the world to use interferon as a nonsurgical treatment of basal cell carcinoma.

Courtesy Scripps Clinic

To date, Dr. Greenway has performed more than 41,000 Mohs surgery cases and has trained 61 fellows who practice in academic and clinical settings. In 2017, he received the Frederic E. Mohs Award from the ACMS at the college’s annual meeting. He is also a past CEO of Scripps Clinic. In this Q&A, Dr. Greenway opens up about what it was like to train with Dr. Mohs, what makes a good Mohs surgeon, and why he’s excited about the future of dermatology.
 

I understand that you first became interested in a medical career after meeting Dr. Carl Jones, a friend of your father who was your Scoutmaster in the Boy Scouts in Georgia. What about Dr. Jones inspired you to pursue a career in medicine?

Dr. Jones was an internist/allergist in Atlanta, where I grew up. His three sons and I were friends. My dad had dealt with several medical problems being injured in World War II and subsequently undergoing a couple of kidney transplantations, so I developed an interest in medicine personally. Even though Dr. Jones was a specialist, he started out as a family doctor like I did, so he was interested in the whole person and all of his or her medical problems as opposed to those related to his specialty only. I traveled with the Boy Scouts to camp at places like Valley Forge in Pennsylvania, and Dr. Jones was involved with the medical set-ups of those large events. That also contributed to my interest in medicine.

As part of your 9-year service in the U.S. Navy, you spent 2 years as the flight surgeon at NAS Atlanta/Dobbins Air Force Base. What was your most memorable experience from that assignment?

Dobbins is a large facility with two Lockheed plants, and the Air Force had built the medical clinic, which was staffed by the Navy. Getting to know some of the active-duty members of the Air Force, the Navy, and the National Guard, and their commitment to our country, was memorable. Jimmy Carter was the president in those days. When he would fly in Dobbins, one of my jobs as the flight surgeon was to be on base when Air Force One landed or departed. One night, we had a DC-9 commercial aircraft coming from Huntsville, Ala., to Atlanta that got caught in a thunderstorm a little above 30,000 feet. Both engines went out and the aircraft essentially became a glider. The pilots tried to land on our runway but unfortunately, they ended up 4 miles short. We were heavily involved in responding to the crash, which was a tragic event. I also learned to fly (second seat) different types of aircraft during my assignment at NAS Atlanta/Dobbins Air Force Base, everything from the large C-5s to Navy fighter jets and helicopters. Coincidentally, Dr. Jones was involved with a couple of free health clinics in Atlanta when I was stationed there. Every Tuesday night, my wife (who is a nurse) and I would volunteer at a clinic in Cabbagetown, which was one of the poorer areas of Atlanta. It was a chance to give back to a group of people who didn’t have a whole lot.

In the middle your dermatology residency at Naval Medical Center San Diego, you were selected by Dr. Mohs for fellowship training in Mohs skin cancer surgery at the University of Wisconsin–Madison. What do you remember most about your training with Dr. Mohs?

Dr. Mohs was a kind, humble man who had this great idea about skin cancer. He was not a dermatologist; he was a general surgeon. The technique he developed was originally called chemosurgery because he put a chemical onto the skin. This was known as the fixed-tissue technique. Then we had a fresh-tissue technique, where we did not use the chemical, but we were able to use local anesthesia right away. That developed into the Mohs surgery we know today. Dr. Mohs did not name it that; he was very humble, but he was very proud of his technique. He was also a very hard worker. On the first day of my fellowship, I started at 7 in the morning and ended at 7 at night. It was the same for the last day of my fellowship. He also had an excellent office staff, many of whom had worked with him for many years. Patients with difficult skin cancers traveled to Madison from all over the world because there weren’t that many Mohs surgery clinics in those days. During the latter part of my fellowship, Michael McCall, MD, and I had the opportunity to remove a skin cancer from the nose of Dr. Mohs. We presented the case at a national conference, and I titled the talk “Mohs Surgery for Mohs’ Nose.”

Early in your career Dr. Mohs asked you to take over his practice, but you accepted an offer to establish the first Mohs surgery office at Scripps in San Diego instead. What convinced you to head West?

After my fellowship, I returned to San Diego to complete my residency with the Navy, where we opened a Mohs surgery clinic. Dr. Mohs came out for the ribbon cutting. During that time, I was taking care of several patients that he had treated in Wisconsin. Through that my wife and I ended up going to dinner with Cecil and Ida Green, philanthropists who made several financial gifts to Scripps Clinic – and for whom Scripps Green Hospital is named. Cecil cofounded Texas Instruments and was knighted by Queen Elizabeth. During dinner, he suggested that I stay in San Diego for a year and work at Scripps after my residency assignment with the Navy. I agreed and have been here ever since.

What do you find most interesting about Mohs surgery?

In Mohs surgery, you’re able to provide not only surgical care to eliminate the tumor, but also the pathology and the reconstruction. That was interesting to me. Dr. Mohs was not that interested in reconstruction. He was more focused on the tumor, in part because with the original fixed-tissue technique you could not do the reconstruction. You had to wait for an extra layer of tissue to separate. But with the fresh-tissue technique, you were able to provide the reconstruction that day. Mohs surgery deals with a subset of tumors that are challenging to treat. That also spiked my academic and clinical interest.

In your opinion, what’s been the most important advance in Mohs surgery to date?

In recent years, immunology has come into play, so now we have teams of clinicians in dermatology, medical oncology, surgery, and other subspecialties providing patients the best of care. In the arena of Mohs surgery itself, in the 1980s, the American College of Mohs Surgery developed a 1-year fellowship program, which enabled us to train many men and women to practice Mohs surgery. Most of them are dermatologists.

Please complete the sentence: “You can tell a good Mohs surgeon by the way he/she ...”

Treats patients, is willing to spend time with them, and shows an interest in them. One of the things we should strive for is to let patients know that they as a person are important; it’s not just the melanoma on their nose. We’re not only dealing with a skin cancer; we’re dealing with a patient who has skin cancer.

For the past 39 years, you have led Hugh Greenway’s Superficial Anatomy and Cutaneous Surgery course, which takes place every January in San Diego. What’s been key to sustaining this training course for nearly 4 decades?

There have been many people involved in its success, so it’s not just me. When I first started my practice, there really was not a focus on anatomy in the general dermatologic community. Dermatologic surgery textbooks contained very little content on surgical anatomy so I developed an interest a putting together a course that would cover some of this material. I met with Terence Davidson, MD, an otolaryngologist who was dean of continuing medical education at the University of California, San Diego. The course includes lectures from experts in many subspecialties and hands-on laboratories using cadavers to work on anatomy and surgical techniques. After about 16 years of doing the course Dr. Davidson told me: “When we started this course, as a group, the head and neck surgeons were the best to do the reconstructions on the face with skin flaps and grafts and layered closures. But now, as a group, the dermatologists are best at doing that.” That’s what we want to hear in medical education.

During the peak of the COVID-19 pandemic, what were your most significant challenges from both a clinical and a personal standpoint?

I’m fortunate to practice at a place like Scripps, where there are many resources to look at what was happening with COVID-19. Clinically, we had to put a lot of things on hold, but we tried our best to keep our cancer patients in particular in the forefront of care. It has been a challenge, but fortunately we have been able to take care of patients after a brief timeout. Many of us remember the polio vaccine back in the 1950s. Having worked overseas and at missionary hospital where we had children die of measles because they were not vaccinated gave me a larger appreciation for the importance of vaccines. I recommend all young physicians who work with me to read, “The Great Influenza: The Story of the Deadliest Pandemic in History,” by John M. Barry, which recounts the 1918 flu epidemic.

Who inspires you most in your work today?

I don’t view what I do as work. Dr. Jones and Dr. Mohs continue to inspire me with what they accomplished during their careers. You have to love people and love patients. Every patient who comes to see me has a story, so I try to understand their story. One of the things I really enjoy is training the young fellows. We train three Mohs fellows per year at Scripps, and it’s a great challenge every day.

What development in dermatology are you most excited about in the next 5 years?

Dermatology will continue to evolve just like all other medical specialties. We’re going to see a large growth in telemedicine, and immunotherapy is playing a key role in dermatologic oncology. What excites me the most in medicine is the young people who enter the field willing to contribute their lives to helping others.

Anyone who practices Mohs micrographic surgery is likely to know the name Hugh Greenway, MD, the longtime head of Mohs and dermatologic surgery at Scripps Clinic in San Diego, who was also recently selected as program director for cutaneous oncology at Scripps MD Anderson Cancer Center in San Diego. He is also a former president of the American College of Mohs Surgery.

After earning his medical degree from the Medical College of Georgia, Augusta, in 1974, Dr. Greenway was fellowship trained in Mohs skin cancer surgery by Frederic E. Mohs, MD, at the University of Wisconsin–Madison. He completed his dermatology residency at the Naval Medical Center San Diego and joined Scripps Clinic in 1983, where he launched the institution’s first Mohs surgery program, as well as a popular annual intensive course in superficial anatomy and cutaneous surgery that bears his name. He was also the first physician in the world to use interferon as a nonsurgical treatment of basal cell carcinoma.

Courtesy Scripps Clinic

To date, Dr. Greenway has performed more than 41,000 Mohs surgery cases and has trained 61 fellows who practice in academic and clinical settings. In 2017, he received the Frederic E. Mohs Award from the ACMS at the college’s annual meeting. He is also a past CEO of Scripps Clinic. In this Q&A, Dr. Greenway opens up about what it was like to train with Dr. Mohs, what makes a good Mohs surgeon, and why he’s excited about the future of dermatology.
 

I understand that you first became interested in a medical career after meeting Dr. Carl Jones, a friend of your father who was your Scoutmaster in the Boy Scouts in Georgia. What about Dr. Jones inspired you to pursue a career in medicine?

Dr. Jones was an internist/allergist in Atlanta, where I grew up. His three sons and I were friends. My dad had dealt with several medical problems being injured in World War II and subsequently undergoing a couple of kidney transplantations, so I developed an interest in medicine personally. Even though Dr. Jones was a specialist, he started out as a family doctor like I did, so he was interested in the whole person and all of his or her medical problems as opposed to those related to his specialty only. I traveled with the Boy Scouts to camp at places like Valley Forge in Pennsylvania, and Dr. Jones was involved with the medical set-ups of those large events. That also contributed to my interest in medicine.

As part of your 9-year service in the U.S. Navy, you spent 2 years as the flight surgeon at NAS Atlanta/Dobbins Air Force Base. What was your most memorable experience from that assignment?

Dobbins is a large facility with two Lockheed plants, and the Air Force had built the medical clinic, which was staffed by the Navy. Getting to know some of the active-duty members of the Air Force, the Navy, and the National Guard, and their commitment to our country, was memorable. Jimmy Carter was the president in those days. When he would fly in Dobbins, one of my jobs as the flight surgeon was to be on base when Air Force One landed or departed. One night, we had a DC-9 commercial aircraft coming from Huntsville, Ala., to Atlanta that got caught in a thunderstorm a little above 30,000 feet. Both engines went out and the aircraft essentially became a glider. The pilots tried to land on our runway but unfortunately, they ended up 4 miles short. We were heavily involved in responding to the crash, which was a tragic event. I also learned to fly (second seat) different types of aircraft during my assignment at NAS Atlanta/Dobbins Air Force Base, everything from the large C-5s to Navy fighter jets and helicopters. Coincidentally, Dr. Jones was involved with a couple of free health clinics in Atlanta when I was stationed there. Every Tuesday night, my wife (who is a nurse) and I would volunteer at a clinic in Cabbagetown, which was one of the poorer areas of Atlanta. It was a chance to give back to a group of people who didn’t have a whole lot.

In the middle your dermatology residency at Naval Medical Center San Diego, you were selected by Dr. Mohs for fellowship training in Mohs skin cancer surgery at the University of Wisconsin–Madison. What do you remember most about your training with Dr. Mohs?

Dr. Mohs was a kind, humble man who had this great idea about skin cancer. He was not a dermatologist; he was a general surgeon. The technique he developed was originally called chemosurgery because he put a chemical onto the skin. This was known as the fixed-tissue technique. Then we had a fresh-tissue technique, where we did not use the chemical, but we were able to use local anesthesia right away. That developed into the Mohs surgery we know today. Dr. Mohs did not name it that; he was very humble, but he was very proud of his technique. He was also a very hard worker. On the first day of my fellowship, I started at 7 in the morning and ended at 7 at night. It was the same for the last day of my fellowship. He also had an excellent office staff, many of whom had worked with him for many years. Patients with difficult skin cancers traveled to Madison from all over the world because there weren’t that many Mohs surgery clinics in those days. During the latter part of my fellowship, Michael McCall, MD, and I had the opportunity to remove a skin cancer from the nose of Dr. Mohs. We presented the case at a national conference, and I titled the talk “Mohs Surgery for Mohs’ Nose.”

Early in your career Dr. Mohs asked you to take over his practice, but you accepted an offer to establish the first Mohs surgery office at Scripps in San Diego instead. What convinced you to head West?

After my fellowship, I returned to San Diego to complete my residency with the Navy, where we opened a Mohs surgery clinic. Dr. Mohs came out for the ribbon cutting. During that time, I was taking care of several patients that he had treated in Wisconsin. Through that my wife and I ended up going to dinner with Cecil and Ida Green, philanthropists who made several financial gifts to Scripps Clinic – and for whom Scripps Green Hospital is named. Cecil cofounded Texas Instruments and was knighted by Queen Elizabeth. During dinner, he suggested that I stay in San Diego for a year and work at Scripps after my residency assignment with the Navy. I agreed and have been here ever since.

What do you find most interesting about Mohs surgery?

In Mohs surgery, you’re able to provide not only surgical care to eliminate the tumor, but also the pathology and the reconstruction. That was interesting to me. Dr. Mohs was not that interested in reconstruction. He was more focused on the tumor, in part because with the original fixed-tissue technique you could not do the reconstruction. You had to wait for an extra layer of tissue to separate. But with the fresh-tissue technique, you were able to provide the reconstruction that day. Mohs surgery deals with a subset of tumors that are challenging to treat. That also spiked my academic and clinical interest.

In your opinion, what’s been the most important advance in Mohs surgery to date?

In recent years, immunology has come into play, so now we have teams of clinicians in dermatology, medical oncology, surgery, and other subspecialties providing patients the best of care. In the arena of Mohs surgery itself, in the 1980s, the American College of Mohs Surgery developed a 1-year fellowship program, which enabled us to train many men and women to practice Mohs surgery. Most of them are dermatologists.

Please complete the sentence: “You can tell a good Mohs surgeon by the way he/she ...”

Treats patients, is willing to spend time with them, and shows an interest in them. One of the things we should strive for is to let patients know that they as a person are important; it’s not just the melanoma on their nose. We’re not only dealing with a skin cancer; we’re dealing with a patient who has skin cancer.

For the past 39 years, you have led Hugh Greenway’s Superficial Anatomy and Cutaneous Surgery course, which takes place every January in San Diego. What’s been key to sustaining this training course for nearly 4 decades?

There have been many people involved in its success, so it’s not just me. When I first started my practice, there really was not a focus on anatomy in the general dermatologic community. Dermatologic surgery textbooks contained very little content on surgical anatomy so I developed an interest a putting together a course that would cover some of this material. I met with Terence Davidson, MD, an otolaryngologist who was dean of continuing medical education at the University of California, San Diego. The course includes lectures from experts in many subspecialties and hands-on laboratories using cadavers to work on anatomy and surgical techniques. After about 16 years of doing the course Dr. Davidson told me: “When we started this course, as a group, the head and neck surgeons were the best to do the reconstructions on the face with skin flaps and grafts and layered closures. But now, as a group, the dermatologists are best at doing that.” That’s what we want to hear in medical education.

During the peak of the COVID-19 pandemic, what were your most significant challenges from both a clinical and a personal standpoint?

I’m fortunate to practice at a place like Scripps, where there are many resources to look at what was happening with COVID-19. Clinically, we had to put a lot of things on hold, but we tried our best to keep our cancer patients in particular in the forefront of care. It has been a challenge, but fortunately we have been able to take care of patients after a brief timeout. Many of us remember the polio vaccine back in the 1950s. Having worked overseas and at missionary hospital where we had children die of measles because they were not vaccinated gave me a larger appreciation for the importance of vaccines. I recommend all young physicians who work with me to read, “The Great Influenza: The Story of the Deadliest Pandemic in History,” by John M. Barry, which recounts the 1918 flu epidemic.

Who inspires you most in your work today?

I don’t view what I do as work. Dr. Jones and Dr. Mohs continue to inspire me with what they accomplished during their careers. You have to love people and love patients. Every patient who comes to see me has a story, so I try to understand their story. One of the things I really enjoy is training the young fellows. We train three Mohs fellows per year at Scripps, and it’s a great challenge every day.

What development in dermatology are you most excited about in the next 5 years?

Dermatology will continue to evolve just like all other medical specialties. We’re going to see a large growth in telemedicine, and immunotherapy is playing a key role in dermatologic oncology. What excites me the most in medicine is the young people who enter the field willing to contribute their lives to helping others.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Acral lentiginous melanoma on the sole of the foot in a 30-year-old Black woman. The depth of the lesion was 2 mm with a positive sentinel lymph node biopsy.

B Nodular melanoma on the shoulder of a 63-year-old Hispanic woman. The depth of the lesion was 5.5 mm with a positive sentinel lymph node biopsy.

Melanoma occurs less frequently in individuals with darker skin types than in lighter skin types but is associated with higher rates of morbidity and mortality in this patient population.^1-7 In the cases shown here (A and B), both patients had advanced melanomas with large primary lesions and lymph node metastases.

Epidemiology

A systematic review by Higgins et al⁶ reported the following on the epidemiology of melanomas in patients with skin of color:

• African Americans have deeper tumors at the time of diagnosis, in addition to increased rates of regionally advanced and distant disease. Lesions generally are located on the lower extremities and have an increased propensity for ulceration. Acral lentiginous melanoma is the most common melanoma subtype found in African American patients.⁶
• In Hispanic individuals, superficial spreading melanoma is the most common melanoma subtype. Lower extremity lesions are more common relative to White individuals. Hispanic individuals have the highest rate of oral cavity melanomas across all ethnic groups.⁶
• In Asian individuals, acral and subungual sites are most common. Specifically, Pacific Islanders have the highest proportion of mucosal melanomas across all ethnic groups.⁶

Key clinical features in people with darker skin tones

Melanomas are found more often on the palms, soles, nail units, oral cavity, and mucosae.6 The melanomas have the same clinical and dermoscopic features found in individuals with lighter skin tones.

Worth noting

Factors that may contribute to the diagnosis of more advanced melanomas in racial/ethnic minorities in the United States include:

• decreased access to health care based on lack of health insurance and low socioeconomic status,
• less awareness of the risk of melanoma among patients and health care providers because melanoma is less common in persons of color, and
• lesions found in areas less likely to be seen in screening examinations, such as the soles of the feet and the oral and genital mucosae.

Health disparity highlight

• In a large US study of 96,953 patients with a diagnosis of cutaneous melanoma from 1992 to 2009, the proportion of later-stage melanoma—stages II to IV—was greater in Black patients compared to White patients.⁷
• Based on this same data set, White patients had the longest survival time (P<.05), followed by Hispanic (P<.05), Asian American/Native American/Pacific Islander (P<.05), and Black (P<.05) patients, respectively.⁷
• In Miami-Dade County, one study of 1690 melanoma cases found that 48% of Black patients had regional or distant disease at presentation compared to 22% of White patients (P=.015).⁵ Analysis of multiple factors found that only race was a significant predictor for late-stage melanoma (P<.001). Black patients in this study were 3 times more likely than others to be diagnosed with melanoma at a late stage (P=.07).⁵
• Black patients in the United States are more likely to have a delayed time from diagnosis to definitive surgery even when controlled for type of health insurance and stage of diagnosis.⁸

Final thoughts

Efforts are needed to overcome these disparities by:

• educating patients with skin of color and their health care providers about the risks of advanced melanoma with the goal of prevention and earlier diagnosis;
• breaking down barriers to care caused by poverty, lack of health insurance, and systemic racism; and
• eliminating factors that lead to delays from diagnosis to definitive surgery.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Acral lentiginous melanoma on the sole of the foot in a 30-year-old Black woman. The depth of the lesion was 2 mm with a positive sentinel lymph node biopsy.

B Nodular melanoma on the shoulder of a 63-year-old Hispanic woman. The depth of the lesion was 5.5 mm with a positive sentinel lymph node biopsy.

Melanoma occurs less frequently in individuals with darker skin types than in lighter skin types but is associated with higher rates of morbidity and mortality in this patient population.^1-7 In the cases shown here (A and B), both patients had advanced melanomas with large primary lesions and lymph node metastases.

Epidemiology

A systematic review by Higgins et al⁶ reported the following on the epidemiology of melanomas in patients with skin of color:

• African Americans have deeper tumors at the time of diagnosis, in addition to increased rates of regionally advanced and distant disease. Lesions generally are located on the lower extremities and have an increased propensity for ulceration. Acral lentiginous melanoma is the most common melanoma subtype found in African American patients.⁶
• In Hispanic individuals, superficial spreading melanoma is the most common melanoma subtype. Lower extremity lesions are more common relative to White individuals. Hispanic individuals have the highest rate of oral cavity melanomas across all ethnic groups.⁶
• In Asian individuals, acral and subungual sites are most common. Specifically, Pacific Islanders have the highest proportion of mucosal melanomas across all ethnic groups.⁶

Key clinical features in people with darker skin tones

Melanomas are found more often on the palms, soles, nail units, oral cavity, and mucosae.6 The melanomas have the same clinical and dermoscopic features found in individuals with lighter skin tones.

Worth noting

Factors that may contribute to the diagnosis of more advanced melanomas in racial/ethnic minorities in the United States include:

• decreased access to health care based on lack of health insurance and low socioeconomic status,
• less awareness of the risk of melanoma among patients and health care providers because melanoma is less common in persons of color, and
• lesions found in areas less likely to be seen in screening examinations, such as the soles of the feet and the oral and genital mucosae.

Health disparity highlight

• In a large US study of 96,953 patients with a diagnosis of cutaneous melanoma from 1992 to 2009, the proportion of later-stage melanoma—stages II to IV—was greater in Black patients compared to White patients.⁷
• Based on this same data set, White patients had the longest survival time (P<.05), followed by Hispanic (P<.05), Asian American/Native American/Pacific Islander (P<.05), and Black (P<.05) patients, respectively.⁷
• In Miami-Dade County, one study of 1690 melanoma cases found that 48% of Black patients had regional or distant disease at presentation compared to 22% of White patients (P=.015).⁵ Analysis of multiple factors found that only race was a significant predictor for late-stage melanoma (P<.001). Black patients in this study were 3 times more likely than others to be diagnosed with melanoma at a late stage (P=.07).⁵
• Black patients in the United States are more likely to have a delayed time from diagnosis to definitive surgery even when controlled for type of health insurance and stage of diagnosis.⁸

Final thoughts

Efforts are needed to overcome these disparities by:

• educating patients with skin of color and their health care providers about the risks of advanced melanoma with the goal of prevention and earlier diagnosis;
• breaking down barriers to care caused by poverty, lack of health insurance, and systemic racism; and
• eliminating factors that lead to delays from diagnosis to definitive surgery.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Acral lentiginous melanoma on the sole of the foot in a 30-year-old Black woman. The depth of the lesion was 2 mm with a positive sentinel lymph node biopsy.

B Nodular melanoma on the shoulder of a 63-year-old Hispanic woman. The depth of the lesion was 5.5 mm with a positive sentinel lymph node biopsy.

Melanoma occurs less frequently in individuals with darker skin types than in lighter skin types but is associated with higher rates of morbidity and mortality in this patient population.^1-7 In the cases shown here (A and B), both patients had advanced melanomas with large primary lesions and lymph node metastases.

Epidemiology

A systematic review by Higgins et al⁶ reported the following on the epidemiology of melanomas in patients with skin of color:

• African Americans have deeper tumors at the time of diagnosis, in addition to increased rates of regionally advanced and distant disease. Lesions generally are located on the lower extremities and have an increased propensity for ulceration. Acral lentiginous melanoma is the most common melanoma subtype found in African American patients.⁶
• In Hispanic individuals, superficial spreading melanoma is the most common melanoma subtype. Lower extremity lesions are more common relative to White individuals. Hispanic individuals have the highest rate of oral cavity melanomas across all ethnic groups.⁶
• In Asian individuals, acral and subungual sites are most common. Specifically, Pacific Islanders have the highest proportion of mucosal melanomas across all ethnic groups.⁶

Key clinical features in people with darker skin tones

Melanomas are found more often on the palms, soles, nail units, oral cavity, and mucosae.6 The melanomas have the same clinical and dermoscopic features found in individuals with lighter skin tones.

Worth noting

Factors that may contribute to the diagnosis of more advanced melanomas in racial/ethnic minorities in the United States include:

• decreased access to health care based on lack of health insurance and low socioeconomic status,
• less awareness of the risk of melanoma among patients and health care providers because melanoma is less common in persons of color, and
• lesions found in areas less likely to be seen in screening examinations, such as the soles of the feet and the oral and genital mucosae.

Health disparity highlight

• In a large US study of 96,953 patients with a diagnosis of cutaneous melanoma from 1992 to 2009, the proportion of later-stage melanoma—stages II to IV—was greater in Black patients compared to White patients.⁷
• Based on this same data set, White patients had the longest survival time (P<.05), followed by Hispanic (P<.05), Asian American/Native American/Pacific Islander (P<.05), and Black (P<.05) patients, respectively.⁷
• In Miami-Dade County, one study of 1690 melanoma cases found that 48% of Black patients had regional or distant disease at presentation compared to 22% of White patients (P=.015).⁵ Analysis of multiple factors found that only race was a significant predictor for late-stage melanoma (P<.001). Black patients in this study were 3 times more likely than others to be diagnosed with melanoma at a late stage (P=.07).⁵
• Black patients in the United States are more likely to have a delayed time from diagnosis to definitive surgery even when controlled for type of health insurance and stage of diagnosis.⁸

Final thoughts

Efforts are needed to overcome these disparities by:

• educating patients with skin of color and their health care providers about the risks of advanced melanoma with the goal of prevention and earlier diagnosis;
• breaking down barriers to care caused by poverty, lack of health insurance, and systemic racism; and
• eliminating factors that lead to delays from diagnosis to definitive surgery.

BOSTON – According to the best available data, solid organ transplant recipients (SOTRs) at highest risk for developing skin cancer are thoracic organ recipients, those aged 50 or older at the time of the transplant, and males.

White patients who meet these criteria should be screening within 2 years after transplant, while Black patients should be screened within 5 years after transplant, Ally-Khan Somani, MD, PhD, said at the annual meeting of the American Academy of Dermatology.

Dr. Somani, director of dermatologic surgery and the division of cutaneous oncology at Indiana University, Indianapolis, based his remarks on consensus screening guidelines assembled from three rounds of Delphi method surveys with 47 dermatologists and 37 transplant physicians, with the goal of establishing skin cancer screening recommendations for SOTRs. Among the dermatologists surveyed, 45% were Mohs surgeons and 55% were general dermatologists.

The panel recommended that the transplant team should perform risk assessment for SOTRs to risk stratify patients for skin cancer screening (high risk vs. low risk). They also proposed that dermatologists perform skin cancer screening by full-body skin examinations, and that SOTRs with a history of skin cancer should continue with routine skin cancer surveillance as recommended by their dermatologists.

Those at low risk for skin cancer include abdominal organ recipients, SOTR age of younger than 50 at time of transplant, and female gender. The guidelines recommend that White, Asian, and Hispanic patients who meet those criteria should be screened within 5 years after transplant, while no consensus was reached for Black patients who meet those criteria.

Based on posttransplant skin cancer incidence rates, risk is increased among males, Whites, thoracic organ recipients, and being age 50 or older, Dr. Somani said. “At our institution, we make sure there’s a good connection between our transplant teams and dermatologists. We recommend rapid referral for suspicious lesions and we educate patients and screen them within 1 year of transplant, or sooner for high-risk patients. Surveillance is increased to every 3 or 4 months for patients with a history of multiple or high-risk cancers or sooner, followed by routine surveillance as recommended by the patient’s dermatologist.”

To risk stratify patients on the development of their first skin cancer post transplantation, researchers developed the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator (SUNTRAC), a prediction tool with a freely available app. Data for the tool were drawn from the Transplant Skin Cancer Network study, a 5-year analysis of 6,340 adult recipients of a first solid organ transplant at 26 transplant centers in the United States. It generates a risk score for SOTRs (low, medium, high, or very high), which informs transplant care providers of a patient’s risk of skin cancer.

Dr. Somani disclosed that he has received grants and funding from Castle Biosciences. He is an adviser to Cook Biotech and a consultant to Sanara MedTech.

BOSTON – According to the best available data, solid organ transplant recipients (SOTRs) at highest risk for developing skin cancer are thoracic organ recipients, those aged 50 or older at the time of the transplant, and males.

White patients who meet these criteria should be screening within 2 years after transplant, while Black patients should be screened within 5 years after transplant, Ally-Khan Somani, MD, PhD, said at the annual meeting of the American Academy of Dermatology.

Dr. Somani, director of dermatologic surgery and the division of cutaneous oncology at Indiana University, Indianapolis, based his remarks on consensus screening guidelines assembled from three rounds of Delphi method surveys with 47 dermatologists and 37 transplant physicians, with the goal of establishing skin cancer screening recommendations for SOTRs. Among the dermatologists surveyed, 45% were Mohs surgeons and 55% were general dermatologists.

The panel recommended that the transplant team should perform risk assessment for SOTRs to risk stratify patients for skin cancer screening (high risk vs. low risk). They also proposed that dermatologists perform skin cancer screening by full-body skin examinations, and that SOTRs with a history of skin cancer should continue with routine skin cancer surveillance as recommended by their dermatologists.

Those at low risk for skin cancer include abdominal organ recipients, SOTR age of younger than 50 at time of transplant, and female gender. The guidelines recommend that White, Asian, and Hispanic patients who meet those criteria should be screened within 5 years after transplant, while no consensus was reached for Black patients who meet those criteria.

Based on posttransplant skin cancer incidence rates, risk is increased among males, Whites, thoracic organ recipients, and being age 50 or older, Dr. Somani said. “At our institution, we make sure there’s a good connection between our transplant teams and dermatologists. We recommend rapid referral for suspicious lesions and we educate patients and screen them within 1 year of transplant, or sooner for high-risk patients. Surveillance is increased to every 3 or 4 months for patients with a history of multiple or high-risk cancers or sooner, followed by routine surveillance as recommended by the patient’s dermatologist.”

To risk stratify patients on the development of their first skin cancer post transplantation, researchers developed the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator (SUNTRAC), a prediction tool with a freely available app. Data for the tool were drawn from the Transplant Skin Cancer Network study, a 5-year analysis of 6,340 adult recipients of a first solid organ transplant at 26 transplant centers in the United States. It generates a risk score for SOTRs (low, medium, high, or very high), which informs transplant care providers of a patient’s risk of skin cancer.

Dr. Somani disclosed that he has received grants and funding from Castle Biosciences. He is an adviser to Cook Biotech and a consultant to Sanara MedTech.

BOSTON – According to the best available data, solid organ transplant recipients (SOTRs) at highest risk for developing skin cancer are thoracic organ recipients, those aged 50 or older at the time of the transplant, and males.

White patients who meet these criteria should be screening within 2 years after transplant, while Black patients should be screened within 5 years after transplant, Ally-Khan Somani, MD, PhD, said at the annual meeting of the American Academy of Dermatology.

Dr. Somani, director of dermatologic surgery and the division of cutaneous oncology at Indiana University, Indianapolis, based his remarks on consensus screening guidelines assembled from three rounds of Delphi method surveys with 47 dermatologists and 37 transplant physicians, with the goal of establishing skin cancer screening recommendations for SOTRs. Among the dermatologists surveyed, 45% were Mohs surgeons and 55% were general dermatologists.

The panel recommended that the transplant team should perform risk assessment for SOTRs to risk stratify patients for skin cancer screening (high risk vs. low risk). They also proposed that dermatologists perform skin cancer screening by full-body skin examinations, and that SOTRs with a history of skin cancer should continue with routine skin cancer surveillance as recommended by their dermatologists.

Those at low risk for skin cancer include abdominal organ recipients, SOTR age of younger than 50 at time of transplant, and female gender. The guidelines recommend that White, Asian, and Hispanic patients who meet those criteria should be screened within 5 years after transplant, while no consensus was reached for Black patients who meet those criteria.

Based on posttransplant skin cancer incidence rates, risk is increased among males, Whites, thoracic organ recipients, and being age 50 or older, Dr. Somani said. “At our institution, we make sure there’s a good connection between our transplant teams and dermatologists. We recommend rapid referral for suspicious lesions and we educate patients and screen them within 1 year of transplant, or sooner for high-risk patients. Surveillance is increased to every 3 or 4 months for patients with a history of multiple or high-risk cancers or sooner, followed by routine surveillance as recommended by the patient’s dermatologist.”

To risk stratify patients on the development of their first skin cancer post transplantation, researchers developed the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator (SUNTRAC), a prediction tool with a freely available app. Data for the tool were drawn from the Transplant Skin Cancer Network study, a 5-year analysis of 6,340 adult recipients of a first solid organ transplant at 26 transplant centers in the United States. It generates a risk score for SOTRs (low, medium, high, or very high), which informs transplant care providers of a patient’s risk of skin cancer.

Dr. Somani disclosed that he has received grants and funding from Castle Biosciences. He is an adviser to Cook Biotech and a consultant to Sanara MedTech.

Bullous pemphigoid, an immune-mediated condition characterized by large, fluid-filled blisters on the skin, is a rare but serious complication of cancer therapy with immune checkpoint inhibitors (ICIs) that may result in treatment interruption or cessation.

Investigators in Boston report that among patients receiving ICIs, being aged 70 years or older and having skin cancer are both significant risk factors for bullous pemphigoid. On the plus side, ICI-induced bullous pemphigoid also appears to be a marker for improved tumor responses to therapy.

In a nested case-control study of 5,636 patients with cancer who received either a programmed death 1 inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo) or a cytotoxic T-lymphocyte–associated protein 4 inhibitor such as ipilimumab (Yervoy), 35 patients (0.6%) developed bullous pemphigoid. The study by Nicole R. LeBoeuf, MD, MPH, from Brigham and Women’s Hospital in Boston and colleagues was published online in JAMA Dermatology.

“What is interesting is that 0.6 is a small number, but we’re seeing bullous pemphigoid at considerably higher frequency than is expected in the general population,” Dr. LeBoeuf said in an interview.

And although bullous pemphigoid has the potential to disrupt ICI therapy, it also appears to be a marker for a favorable tumor response, the investigators found.

Their findings suggest that management of bullous pemphigoid for patients receiving ICIs should focus on early identification and management with therapies directed at the specific toxicity, Dr. LeBoeuf said.

“When you make a specific diagnosis like bullous pemphigoid, then you can treat that specific disease with very targeted therapies, such as omalizumab or dupilumab or rituximab – things that are not globally immune suppressing like steroid or other T-cell–depleting agents. Studies have shown that depleting B cells with anti-CD20 agents is not detrimental to immune checkpoint inhibitor therapy,” she said.
 

Dermatologic AEs common

About 40% of patients with cancer treated with ICIs experience immune-related dermatologic adverse events (AEs) that can range from mild rashes and hair and nail changes to uncommon but life-threatening complications, such as Stevens-Johnson syndrome, a form of toxic epidermal necrolysis, according to members of a European Academy of Dermatology and Venereology task force.

“The desirable, immune-mediated oncologic response is often achieved at the cost of immune-related adverse events (irAEs) that may potentially affect any organ system,” they wrote in a position statement on the management of ICI-derived dermatologic adverse events.

Dr. LeBoeuf and colleagues note that, while reported risk factors for idiopathic bullous pemphigoid include advanced age, type 2 diabetes, use of dipeptidyl peptidase-4 inhibitors, cerebrovascular disease, and neurocognitive disease, risk factors for bullous pemphigoid and other adverse dermatologic events associated with ICIs are less well known.
 

Study details

To identify risk factors for bullous pemphigoid in patients receiving ICI, the investigators performed a case-control study nested within a retrospective cohort study.

They evaluated records for all patients in the three Harvard-affiliated hospitals to identify patients with ICI-associated bullous pemphigoid from October 2014 through December 2020. Control persons were all patients in the Dana-Farber cancer registry who received ICIs during the study period.

The investigators chose age at ICI initiation (69 years and younger or 70 years and older), sex, ICI agents, and cancer type as potential risk factors.

They used propensity score matching based on age, cancer type, ICI agent, and number of ICI cycles to match two control persons with each case patient.

Of the 5,636 patients treated with ICIs during the study period, 35 (0.6%) developed bullous pemphigoid. The median age was 72.8 years, and 71.4% were men.

In a multivariate logistic regression model that included 2,955 patients with complete data in the cancer registry, factors significantly associated with developing bullous pemphigoid included age 70 years or older (odds ratio, 2.32; P = .01), having melanoma (OR, 3.21; P < .001), and having nonmelanoma skin cancer (OR, 8.32; P < .001).

In comparing the 35 case patients with their matched control patients, a complete or partial response at first restaging imaging was significantly associated with developing bullous pemphigoid (OR, 3.37; P = .01). In addition, there was a higher likelihood of tumor responses to ICIs among patients with bullous pemphigoid, compared with matched control patients (objective response rate, 82.9% vs. 61.4%; P = .03).
 

Prudent toxicity management

Ryan Sullivan, MD, who treats patients with skin cancer at Massachusetts General Hospital Cancer Center, Boston, but was not involved in the study, commented that the findings raise questions about the relationship between skin cancers and immune-related adverse events.

“It is compelling that bullous pemphigoid is a skin toxicity and is more common to happen in skin cancer patients,” he noted. “That’s a very interesting finding, and the reason that it’s interesting is that it’s harder to understand why a presumably antibody-mediated side effect would be more likely to have that cross-reactivity where the tumor started and where the toxicity happened,” he said in an interview.

He noted that the benefits of ICIs for patients with skin cancers far outweigh the risks of dermatologic adverse events such as bullous pemphigoid and that ICI-associated events require judicious management.

“This is true across the spectrum of toxicities: There are clear manifestations of toxicity that we should be more thoughtful about what’s driving them, more thoughtful about what it is, and more thoughtful about treating them, other than just pouring steroids into patients in industrial doses and hoping that everything’s going to be OK,” he said.

No funding source for the study was reported. Dr. LeBoeuf reported receiving grants from the National Institutes of Health National Cancer Institute during the conduct of the study and personal fees for serving as a consultant for several companies outside the study. Coauthor Arash Mostaghimi, MD, MPA, MPH, is associate editor of JAMA Dermatology but was not involved in study selection or evaluation for publication. Dr. Sullivan disclosed consulting for ICI makers Bristol-Myers Squibb and Merck.

A version of this article first appeared on Medscape.com.

Bullous pemphigoid, an immune-mediated condition characterized by large, fluid-filled blisters on the skin, is a rare but serious complication of cancer therapy with immune checkpoint inhibitors (ICIs) that may result in treatment interruption or cessation.

Investigators in Boston report that among patients receiving ICIs, being aged 70 years or older and having skin cancer are both significant risk factors for bullous pemphigoid. On the plus side, ICI-induced bullous pemphigoid also appears to be a marker for improved tumor responses to therapy.

In a nested case-control study of 5,636 patients with cancer who received either a programmed death 1 inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo) or a cytotoxic T-lymphocyte–associated protein 4 inhibitor such as ipilimumab (Yervoy), 35 patients (0.6%) developed bullous pemphigoid. The study by Nicole R. LeBoeuf, MD, MPH, from Brigham and Women’s Hospital in Boston and colleagues was published online in JAMA Dermatology.

“What is interesting is that 0.6 is a small number, but we’re seeing bullous pemphigoid at considerably higher frequency than is expected in the general population,” Dr. LeBoeuf said in an interview.

And although bullous pemphigoid has the potential to disrupt ICI therapy, it also appears to be a marker for a favorable tumor response, the investigators found.

Their findings suggest that management of bullous pemphigoid for patients receiving ICIs should focus on early identification and management with therapies directed at the specific toxicity, Dr. LeBoeuf said.

“When you make a specific diagnosis like bullous pemphigoid, then you can treat that specific disease with very targeted therapies, such as omalizumab or dupilumab or rituximab – things that are not globally immune suppressing like steroid or other T-cell–depleting agents. Studies have shown that depleting B cells with anti-CD20 agents is not detrimental to immune checkpoint inhibitor therapy,” she said.
 

Dermatologic AEs common

About 40% of patients with cancer treated with ICIs experience immune-related dermatologic adverse events (AEs) that can range from mild rashes and hair and nail changes to uncommon but life-threatening complications, such as Stevens-Johnson syndrome, a form of toxic epidermal necrolysis, according to members of a European Academy of Dermatology and Venereology task force.

“The desirable, immune-mediated oncologic response is often achieved at the cost of immune-related adverse events (irAEs) that may potentially affect any organ system,” they wrote in a position statement on the management of ICI-derived dermatologic adverse events.

Dr. LeBoeuf and colleagues note that, while reported risk factors for idiopathic bullous pemphigoid include advanced age, type 2 diabetes, use of dipeptidyl peptidase-4 inhibitors, cerebrovascular disease, and neurocognitive disease, risk factors for bullous pemphigoid and other adverse dermatologic events associated with ICIs are less well known.
 

Study details

To identify risk factors for bullous pemphigoid in patients receiving ICI, the investigators performed a case-control study nested within a retrospective cohort study.

They evaluated records for all patients in the three Harvard-affiliated hospitals to identify patients with ICI-associated bullous pemphigoid from October 2014 through December 2020. Control persons were all patients in the Dana-Farber cancer registry who received ICIs during the study period.

The investigators chose age at ICI initiation (69 years and younger or 70 years and older), sex, ICI agents, and cancer type as potential risk factors.

They used propensity score matching based on age, cancer type, ICI agent, and number of ICI cycles to match two control persons with each case patient.

Of the 5,636 patients treated with ICIs during the study period, 35 (0.6%) developed bullous pemphigoid. The median age was 72.8 years, and 71.4% were men.

In a multivariate logistic regression model that included 2,955 patients with complete data in the cancer registry, factors significantly associated with developing bullous pemphigoid included age 70 years or older (odds ratio, 2.32; P = .01), having melanoma (OR, 3.21; P < .001), and having nonmelanoma skin cancer (OR, 8.32; P < .001).

In comparing the 35 case patients with their matched control patients, a complete or partial response at first restaging imaging was significantly associated with developing bullous pemphigoid (OR, 3.37; P = .01). In addition, there was a higher likelihood of tumor responses to ICIs among patients with bullous pemphigoid, compared with matched control patients (objective response rate, 82.9% vs. 61.4%; P = .03).
 

Prudent toxicity management

Ryan Sullivan, MD, who treats patients with skin cancer at Massachusetts General Hospital Cancer Center, Boston, but was not involved in the study, commented that the findings raise questions about the relationship between skin cancers and immune-related adverse events.

“It is compelling that bullous pemphigoid is a skin toxicity and is more common to happen in skin cancer patients,” he noted. “That’s a very interesting finding, and the reason that it’s interesting is that it’s harder to understand why a presumably antibody-mediated side effect would be more likely to have that cross-reactivity where the tumor started and where the toxicity happened,” he said in an interview.

He noted that the benefits of ICIs for patients with skin cancers far outweigh the risks of dermatologic adverse events such as bullous pemphigoid and that ICI-associated events require judicious management.

“This is true across the spectrum of toxicities: There are clear manifestations of toxicity that we should be more thoughtful about what’s driving them, more thoughtful about what it is, and more thoughtful about treating them, other than just pouring steroids into patients in industrial doses and hoping that everything’s going to be OK,” he said.

No funding source for the study was reported. Dr. LeBoeuf reported receiving grants from the National Institutes of Health National Cancer Institute during the conduct of the study and personal fees for serving as a consultant for several companies outside the study. Coauthor Arash Mostaghimi, MD, MPA, MPH, is associate editor of JAMA Dermatology but was not involved in study selection or evaluation for publication. Dr. Sullivan disclosed consulting for ICI makers Bristol-Myers Squibb and Merck.

A version of this article first appeared on Medscape.com.

Bullous pemphigoid, an immune-mediated condition characterized by large, fluid-filled blisters on the skin, is a rare but serious complication of cancer therapy with immune checkpoint inhibitors (ICIs) that may result in treatment interruption or cessation.

Investigators in Boston report that among patients receiving ICIs, being aged 70 years or older and having skin cancer are both significant risk factors for bullous pemphigoid. On the plus side, ICI-induced bullous pemphigoid also appears to be a marker for improved tumor responses to therapy.

In a nested case-control study of 5,636 patients with cancer who received either a programmed death 1 inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo) or a cytotoxic T-lymphocyte–associated protein 4 inhibitor such as ipilimumab (Yervoy), 35 patients (0.6%) developed bullous pemphigoid. The study by Nicole R. LeBoeuf, MD, MPH, from Brigham and Women’s Hospital in Boston and colleagues was published online in JAMA Dermatology.

“What is interesting is that 0.6 is a small number, but we’re seeing bullous pemphigoid at considerably higher frequency than is expected in the general population,” Dr. LeBoeuf said in an interview.

And although bullous pemphigoid has the potential to disrupt ICI therapy, it also appears to be a marker for a favorable tumor response, the investigators found.

Their findings suggest that management of bullous pemphigoid for patients receiving ICIs should focus on early identification and management with therapies directed at the specific toxicity, Dr. LeBoeuf said.

“When you make a specific diagnosis like bullous pemphigoid, then you can treat that specific disease with very targeted therapies, such as omalizumab or dupilumab or rituximab – things that are not globally immune suppressing like steroid or other T-cell–depleting agents. Studies have shown that depleting B cells with anti-CD20 agents is not detrimental to immune checkpoint inhibitor therapy,” she said.
 

Dermatologic AEs common

About 40% of patients with cancer treated with ICIs experience immune-related dermatologic adverse events (AEs) that can range from mild rashes and hair and nail changes to uncommon but life-threatening complications, such as Stevens-Johnson syndrome, a form of toxic epidermal necrolysis, according to members of a European Academy of Dermatology and Venereology task force.

“The desirable, immune-mediated oncologic response is often achieved at the cost of immune-related adverse events (irAEs) that may potentially affect any organ system,” they wrote in a position statement on the management of ICI-derived dermatologic adverse events.

Dr. LeBoeuf and colleagues note that, while reported risk factors for idiopathic bullous pemphigoid include advanced age, type 2 diabetes, use of dipeptidyl peptidase-4 inhibitors, cerebrovascular disease, and neurocognitive disease, risk factors for bullous pemphigoid and other adverse dermatologic events associated with ICIs are less well known.
 

Study details

To identify risk factors for bullous pemphigoid in patients receiving ICI, the investigators performed a case-control study nested within a retrospective cohort study.

They evaluated records for all patients in the three Harvard-affiliated hospitals to identify patients with ICI-associated bullous pemphigoid from October 2014 through December 2020. Control persons were all patients in the Dana-Farber cancer registry who received ICIs during the study period.

The investigators chose age at ICI initiation (69 years and younger or 70 years and older), sex, ICI agents, and cancer type as potential risk factors.

They used propensity score matching based on age, cancer type, ICI agent, and number of ICI cycles to match two control persons with each case patient.

Of the 5,636 patients treated with ICIs during the study period, 35 (0.6%) developed bullous pemphigoid. The median age was 72.8 years, and 71.4% were men.

In a multivariate logistic regression model that included 2,955 patients with complete data in the cancer registry, factors significantly associated with developing bullous pemphigoid included age 70 years or older (odds ratio, 2.32; P = .01), having melanoma (OR, 3.21; P < .001), and having nonmelanoma skin cancer (OR, 8.32; P < .001).

In comparing the 35 case patients with their matched control patients, a complete or partial response at first restaging imaging was significantly associated with developing bullous pemphigoid (OR, 3.37; P = .01). In addition, there was a higher likelihood of tumor responses to ICIs among patients with bullous pemphigoid, compared with matched control patients (objective response rate, 82.9% vs. 61.4%; P = .03).
 

Prudent toxicity management

Ryan Sullivan, MD, who treats patients with skin cancer at Massachusetts General Hospital Cancer Center, Boston, but was not involved in the study, commented that the findings raise questions about the relationship between skin cancers and immune-related adverse events.

“It is compelling that bullous pemphigoid is a skin toxicity and is more common to happen in skin cancer patients,” he noted. “That’s a very interesting finding, and the reason that it’s interesting is that it’s harder to understand why a presumably antibody-mediated side effect would be more likely to have that cross-reactivity where the tumor started and where the toxicity happened,” he said in an interview.

He noted that the benefits of ICIs for patients with skin cancers far outweigh the risks of dermatologic adverse events such as bullous pemphigoid and that ICI-associated events require judicious management.

“This is true across the spectrum of toxicities: There are clear manifestations of toxicity that we should be more thoughtful about what’s driving them, more thoughtful about what it is, and more thoughtful about treating them, other than just pouring steroids into patients in industrial doses and hoping that everything’s going to be OK,” he said.

No funding source for the study was reported. Dr. LeBoeuf reported receiving grants from the National Institutes of Health National Cancer Institute during the conduct of the study and personal fees for serving as a consultant for several companies outside the study. Coauthor Arash Mostaghimi, MD, MPA, MPH, is associate editor of JAMA Dermatology but was not involved in study selection or evaluation for publication. Dr. Sullivan disclosed consulting for ICI makers Bristol-Myers Squibb and Merck.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents, objective clinical responses occurred with a customized cell therapy based on T cells extracted directly from tumor tissue.

The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.

The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.

“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).

He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.

However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.

The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.

“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
 

Patient-derived product

Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.

Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
 

Details from clinical trial

At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.

These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.

Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.

After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.

Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.

The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.

All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.

The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.

“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.

The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
 

Remaining questions, next steps

Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.

“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.

Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.

Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.

The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.

A version of this article first appeared on Medscape.com.

Screening for melanoma at the primary care level is associated with significant increases in the detection of in situ and invasive thin melanomas but not thicker, more worrisome disease, new research shows.

Without a corresponding decrease in melanoma mortality, an increase in the detection of those thin melanomas “raises the concern that early detection efforts, such as visual skin screening, may result in overdiagnosis,” the study authors wrote. “The value of a cancer screening program should most rigorously be measured not by the number of new, early cancers detected, but by its impact on the development of late-stage disease and its associated morbidity, cost, and mortality.”

The research, published in JAMA Dermatology, has reignited the controversy over the benefits and harms of primary care skin cancer screening, garnering two editorials that reflect different sides of the debate.

In one, Robert A. Swerlick, MD, pointed out that, “despite public messaging to the contrary, to my knowledge there is no evidence that routine skin examinations have any effect on melanoma mortality.

“The stage shift to smaller tumors should not be viewed as success and is very strong evidence of overdiagnosis,” wrote Dr. Swerlick, of the department of dermatology, Emory University, Atlanta.

The other editorial, however, argued that routine screening saves lives. “Most melanoma deaths are because of stage I disease, with an estimated 3%-15% of thin melanomas (≤ 1 mm) being lethal,” wrote a trio of editorialists from Oregon Health & Science University, Portland.

When considering the high mutation rate associated with melanoma and the current limits of treatment options, early diagnosis becomes “particularly important and counterbalances the risk of overdiagnosis,” the editorialists asserted.

Primary care screening study

The new findings come from an observational study of a quality improvement initiative conducted at the University of Pittsburgh Medical Center system between 2014 and 2018, in which primary care clinicians were offered training in melanoma identification through skin examination and were encouraged to offer annual skin cancer screening to patients aged 35 years and older.

Of 595,799 eligible patients, 144,851 (24.3%) were screened at least once during the study period. Those who received screening were more likely than unscreened patients to be older (median age, 59 vs. 55 years), women, and non-Hispanic White persons.

During a follow-up of 5 years, the researchers found that patients who received screening were significantly more likely than unscreened patients to be diagnosed with in situ melanoma (incidence, 30.4 vs. 14.4; hazard ratio, 2.6; P < .001) or thin invasive melanoma (incidence, 24.5 vs. 16.1; HR, 1.8; P < .001), after adjusting for factors that included age, sex, and race.

The screened patients were also more likely than unscreened patients to be diagnosed with in situ interval melanomas, defined as melanomas occurring at least 60 days after initial screening (incidence, 26.7 vs. 12.9; HR, 2.1; P < .001), as well as thin invasive interval melanomas (incidence, 18.5 vs. 14.4; HR, 1.3; P = .03).

The 60-day interval was included to account for the possible time to referral to a specialist for definitive diagnosis, the authors explained.

The incidence of the detection of melanomas thicker than 4 mm was lower in screened versus unscreened patients, but the difference was not statistically significant for all melanomas (2.7 vs. 3.3; HR, 0.8; P = .38) or interval melanomas (1.5 vs. 2.7; HR, 0.6; P = .15).
 

Experts weigh in

Although the follow-up period was of 5 years, not all patients were followed that long after undergoing screening. For instance, for some patients, follow-up occurred only 1 year after they had been screened.

The study’s senior author, Laura K. Ferris, MD, PhD, of the department of dermatology, University of Pittsburgh, noted that a longer follow-up could shift the results.

“When you look at the curves in our figures, you do start to see them separate more and more over time for the thicker melanomas,” Dr. Ferris said in an interview. “I do suspect that, if we followed patients longer, we might start to see a more significant difference.”

The findings nevertheless add to evidence that although routine screening substantially increases the detection of melanomas overall, these melanomas are often not the ones doctors are most worried about or that increase a person’s risk of mortality, Dr. Ferris noted.

When it comes to melanoma screening, balancing the risks and benefits is key. One major downside, Dr. Ferris said, is in regard to the burden such screening could place on the health care system, with potentially unproductive screenings causing delays in care for patients with more urgent needs.

“We are undersupplied in the dermatology workforce, and there is often a long wait to see dermatologists, so we really want to make sure, as trained professionals, that patients have access to us,” she said. “If we’re doing something that doesn’t have proven benefit and is increasing the wait time, that will come at the expense of other patients’ access.”

Costs involved in skin biopsies and excisions of borderline lesions as well as the potential to increase patients’ anxiety represent other important considerations, Dr. Ferris noted.

However, Sancy A. Leachman, MD, PhD, a coauthor of the editorial in favor of screening, said in an interview that “at the individual level, there are an almost infinite number of individual circumstances that could lead a person to decide that the potential benefits outweigh the harms.”

According to Dr. Leachman, who is chair of the department of dermatology, Oregon Health & Science University, these individual priorities may not align with those of the various decision-makers or with guidelines, such as those from the U.S. Preventive Services Task Force, which gives visual skin cancer screening of asymptomatic patients an “I” rating, indicating “insufficient evidence.”

“Many federal agencies and payer groups focus on minimizing costs and optimizing outcomes,” Dr. Leachman and coauthors wrote. As the only professional advocates for individual patients, physicians “have a responsibility to assure that the best interests of patients are served.”

The study was funded by the University of Pittsburgh Melanoma and Skin Cancer Program. Dr. Ferris and Dr. Swerlick disclosed no relevant financial relationships. Dr. Leachman is the principal investigator for War on Melanoma, an early-detection program in Oregon.

A version of this article first appeared on Medscape.com.

Screening for melanoma at the primary care level is associated with significant increases in the detection of in situ and invasive thin melanomas but not thicker, more worrisome disease, new research shows.

Without a corresponding decrease in melanoma mortality, an increase in the detection of those thin melanomas “raises the concern that early detection efforts, such as visual skin screening, may result in overdiagnosis,” the study authors wrote. “The value of a cancer screening program should most rigorously be measured not by the number of new, early cancers detected, but by its impact on the development of late-stage disease and its associated morbidity, cost, and mortality.”

The research, published in JAMA Dermatology, has reignited the controversy over the benefits and harms of primary care skin cancer screening, garnering two editorials that reflect different sides of the debate.

In one, Robert A. Swerlick, MD, pointed out that, “despite public messaging to the contrary, to my knowledge there is no evidence that routine skin examinations have any effect on melanoma mortality.

“The stage shift to smaller tumors should not be viewed as success and is very strong evidence of overdiagnosis,” wrote Dr. Swerlick, of the department of dermatology, Emory University, Atlanta.

The other editorial, however, argued that routine screening saves lives. “Most melanoma deaths are because of stage I disease, with an estimated 3%-15% of thin melanomas (≤ 1 mm) being lethal,” wrote a trio of editorialists from Oregon Health & Science University, Portland.

When considering the high mutation rate associated with melanoma and the current limits of treatment options, early diagnosis becomes “particularly important and counterbalances the risk of overdiagnosis,” the editorialists asserted.

Primary care screening study

The new findings come from an observational study of a quality improvement initiative conducted at the University of Pittsburgh Medical Center system between 2014 and 2018, in which primary care clinicians were offered training in melanoma identification through skin examination and were encouraged to offer annual skin cancer screening to patients aged 35 years and older.

Of 595,799 eligible patients, 144,851 (24.3%) were screened at least once during the study period. Those who received screening were more likely than unscreened patients to be older (median age, 59 vs. 55 years), women, and non-Hispanic White persons.

During a follow-up of 5 years, the researchers found that patients who received screening were significantly more likely than unscreened patients to be diagnosed with in situ melanoma (incidence, 30.4 vs. 14.4; hazard ratio, 2.6; P < .001) or thin invasive melanoma (incidence, 24.5 vs. 16.1; HR, 1.8; P < .001), after adjusting for factors that included age, sex, and race.

The screened patients were also more likely than unscreened patients to be diagnosed with in situ interval melanomas, defined as melanomas occurring at least 60 days after initial screening (incidence, 26.7 vs. 12.9; HR, 2.1; P < .001), as well as thin invasive interval melanomas (incidence, 18.5 vs. 14.4; HR, 1.3; P = .03).

The 60-day interval was included to account for the possible time to referral to a specialist for definitive diagnosis, the authors explained.

The incidence of the detection of melanomas thicker than 4 mm was lower in screened versus unscreened patients, but the difference was not statistically significant for all melanomas (2.7 vs. 3.3; HR, 0.8; P = .38) or interval melanomas (1.5 vs. 2.7; HR, 0.6; P = .15).
 

Experts weigh in

Although the follow-up period was of 5 years, not all patients were followed that long after undergoing screening. For instance, for some patients, follow-up occurred only 1 year after they had been screened.

The study’s senior author, Laura K. Ferris, MD, PhD, of the department of dermatology, University of Pittsburgh, noted that a longer follow-up could shift the results.

“When you look at the curves in our figures, you do start to see them separate more and more over time for the thicker melanomas,” Dr. Ferris said in an interview. “I do suspect that, if we followed patients longer, we might start to see a more significant difference.”

The findings nevertheless add to evidence that although routine screening substantially increases the detection of melanomas overall, these melanomas are often not the ones doctors are most worried about or that increase a person’s risk of mortality, Dr. Ferris noted.

When it comes to melanoma screening, balancing the risks and benefits is key. One major downside, Dr. Ferris said, is in regard to the burden such screening could place on the health care system, with potentially unproductive screenings causing delays in care for patients with more urgent needs.

“We are undersupplied in the dermatology workforce, and there is often a long wait to see dermatologists, so we really want to make sure, as trained professionals, that patients have access to us,” she said. “If we’re doing something that doesn’t have proven benefit and is increasing the wait time, that will come at the expense of other patients’ access.”

Costs involved in skin biopsies and excisions of borderline lesions as well as the potential to increase patients’ anxiety represent other important considerations, Dr. Ferris noted.

However, Sancy A. Leachman, MD, PhD, a coauthor of the editorial in favor of screening, said in an interview that “at the individual level, there are an almost infinite number of individual circumstances that could lead a person to decide that the potential benefits outweigh the harms.”

According to Dr. Leachman, who is chair of the department of dermatology, Oregon Health & Science University, these individual priorities may not align with those of the various decision-makers or with guidelines, such as those from the U.S. Preventive Services Task Force, which gives visual skin cancer screening of asymptomatic patients an “I” rating, indicating “insufficient evidence.”

“Many federal agencies and payer groups focus on minimizing costs and optimizing outcomes,” Dr. Leachman and coauthors wrote. As the only professional advocates for individual patients, physicians “have a responsibility to assure that the best interests of patients are served.”

The study was funded by the University of Pittsburgh Melanoma and Skin Cancer Program. Dr. Ferris and Dr. Swerlick disclosed no relevant financial relationships. Dr. Leachman is the principal investigator for War on Melanoma, an early-detection program in Oregon.

A version of this article first appeared on Medscape.com.

Screening for melanoma at the primary care level is associated with significant increases in the detection of in situ and invasive thin melanomas but not thicker, more worrisome disease, new research shows.

Without a corresponding decrease in melanoma mortality, an increase in the detection of those thin melanomas “raises the concern that early detection efforts, such as visual skin screening, may result in overdiagnosis,” the study authors wrote. “The value of a cancer screening program should most rigorously be measured not by the number of new, early cancers detected, but by its impact on the development of late-stage disease and its associated morbidity, cost, and mortality.”

The research, published in JAMA Dermatology, has reignited the controversy over the benefits and harms of primary care skin cancer screening, garnering two editorials that reflect different sides of the debate.

In one, Robert A. Swerlick, MD, pointed out that, “despite public messaging to the contrary, to my knowledge there is no evidence that routine skin examinations have any effect on melanoma mortality.

“The stage shift to smaller tumors should not be viewed as success and is very strong evidence of overdiagnosis,” wrote Dr. Swerlick, of the department of dermatology, Emory University, Atlanta.

The other editorial, however, argued that routine screening saves lives. “Most melanoma deaths are because of stage I disease, with an estimated 3%-15% of thin melanomas (≤ 1 mm) being lethal,” wrote a trio of editorialists from Oregon Health & Science University, Portland.

When considering the high mutation rate associated with melanoma and the current limits of treatment options, early diagnosis becomes “particularly important and counterbalances the risk of overdiagnosis,” the editorialists asserted.

Primary care screening study

The new findings come from an observational study of a quality improvement initiative conducted at the University of Pittsburgh Medical Center system between 2014 and 2018, in which primary care clinicians were offered training in melanoma identification through skin examination and were encouraged to offer annual skin cancer screening to patients aged 35 years and older.

Of 595,799 eligible patients, 144,851 (24.3%) were screened at least once during the study period. Those who received screening were more likely than unscreened patients to be older (median age, 59 vs. 55 years), women, and non-Hispanic White persons.

During a follow-up of 5 years, the researchers found that patients who received screening were significantly more likely than unscreened patients to be diagnosed with in situ melanoma (incidence, 30.4 vs. 14.4; hazard ratio, 2.6; P < .001) or thin invasive melanoma (incidence, 24.5 vs. 16.1; HR, 1.8; P < .001), after adjusting for factors that included age, sex, and race.

The screened patients were also more likely than unscreened patients to be diagnosed with in situ interval melanomas, defined as melanomas occurring at least 60 days after initial screening (incidence, 26.7 vs. 12.9; HR, 2.1; P < .001), as well as thin invasive interval melanomas (incidence, 18.5 vs. 14.4; HR, 1.3; P = .03).

The 60-day interval was included to account for the possible time to referral to a specialist for definitive diagnosis, the authors explained.

The incidence of the detection of melanomas thicker than 4 mm was lower in screened versus unscreened patients, but the difference was not statistically significant for all melanomas (2.7 vs. 3.3; HR, 0.8; P = .38) or interval melanomas (1.5 vs. 2.7; HR, 0.6; P = .15).
 

Experts weigh in

Although the follow-up period was of 5 years, not all patients were followed that long after undergoing screening. For instance, for some patients, follow-up occurred only 1 year after they had been screened.

The study’s senior author, Laura K. Ferris, MD, PhD, of the department of dermatology, University of Pittsburgh, noted that a longer follow-up could shift the results.

“When you look at the curves in our figures, you do start to see them separate more and more over time for the thicker melanomas,” Dr. Ferris said in an interview. “I do suspect that, if we followed patients longer, we might start to see a more significant difference.”

The findings nevertheless add to evidence that although routine screening substantially increases the detection of melanomas overall, these melanomas are often not the ones doctors are most worried about or that increase a person’s risk of mortality, Dr. Ferris noted.

When it comes to melanoma screening, balancing the risks and benefits is key. One major downside, Dr. Ferris said, is in regard to the burden such screening could place on the health care system, with potentially unproductive screenings causing delays in care for patients with more urgent needs.

“We are undersupplied in the dermatology workforce, and there is often a long wait to see dermatologists, so we really want to make sure, as trained professionals, that patients have access to us,” she said. “If we’re doing something that doesn’t have proven benefit and is increasing the wait time, that will come at the expense of other patients’ access.”

Costs involved in skin biopsies and excisions of borderline lesions as well as the potential to increase patients’ anxiety represent other important considerations, Dr. Ferris noted.

However, Sancy A. Leachman, MD, PhD, a coauthor of the editorial in favor of screening, said in an interview that “at the individual level, there are an almost infinite number of individual circumstances that could lead a person to decide that the potential benefits outweigh the harms.”

According to Dr. Leachman, who is chair of the department of dermatology, Oregon Health & Science University, these individual priorities may not align with those of the various decision-makers or with guidelines, such as those from the U.S. Preventive Services Task Force, which gives visual skin cancer screening of asymptomatic patients an “I” rating, indicating “insufficient evidence.”

“Many federal agencies and payer groups focus on minimizing costs and optimizing outcomes,” Dr. Leachman and coauthors wrote. As the only professional advocates for individual patients, physicians “have a responsibility to assure that the best interests of patients are served.”

The study was funded by the University of Pittsburgh Melanoma and Skin Cancer Program. Dr. Ferris and Dr. Swerlick disclosed no relevant financial relationships. Dr. Leachman is the principal investigator for War on Melanoma, an early-detection program in Oregon.

A version of this article first appeared on Medscape.com.

BOSTON – Although skin biopsy remains the gold standard for diagnosing early-stage melanoma, advances in genetic expression profiling are helping dermatologists provide a nuanced approach to managing suspicious lesions.

One such test, the Pigmented Lesional Assay (PLA) uses adhesive patches applied to lesions of concern at the bedside to extract RNA from the stratum corneum to help determine the risk for melanoma.

At the annual meeting of the American Academy of Dermatology, Caroline C. Kim, MD, director of melanoma and pigmented lesion clinics at Newton Wellesley Dermatology, Wellesley Hills, Mass., and Tufts Medical Center, Boston, spoke about the PLA, which uses genetic expression profiling to measure the expression level of specific genes that are associated with melanoma: PRAME (preferentially expressed antigen in melanoma) and LINC00518 (LINC). There are four possible results of the test: Aberrant expression of both LINC and PRAME (high risk); aberrant expression of a single gene (moderate risk); aberrant expression of neither gene (low risk); or inconclusive.

Validation data have shown a sensitivity of 91% and a specificity of 69% for the PLA, with a 99% negative predictive value; so a lesion that tested negative by PLA has a less than 1% chance of being melanoma. In addition, a study published in 2020 found that the addition of TERT (telomerase reverse transcriptase) mutation analyses increased the sensitivity of the PLA to 97%.

While the high negative predictive value is helpful to consider in clinical scenarios to rule-out melanoma for borderline lesions, one must consider the positive predictive value as well and how this may impact clinical care, Dr. Kim said. In a study examining outcomes of 381 lesions, 51 were PLA positive (single or double) and were biopsied, of which 19 (37%) revealed a melanoma diagnosis. In a large U.S. registry study of 3,418 lesions, 324 lesions that were PLA double positive were biopsied, with 18.7% revealing a melanoma diagnosis.

“No test is perfect, and this applies to PLA, even if you get a double-positive or double-negative test result,” Dr. Kim said. “You want to make sure that patients are aware of false positives and negatives. However, PLA could be an additional piece of data to inform your decision to proceed with biopsy on select borderline suspicious pigmented lesions. More studies are needed to better understand the approach to single- and double-positive PLA results.”

The PLA kit contains adhesive patches and supplies and a FedEx envelope for return to DermTech, the test’s manufacturer, for processing. The patches can be applied to lesions at least 4 mm in diameter; multiple kits are recommended for those greater than 16 mm in diameter. The test is not validated for lesions located on mucous membranes, palms, soles, nails, or on ulcerated or bleeding lesions, nor for those that have been previously biopsied. It is also not validated for use in pediatric patients or in those with skin types IV or higher. Results are returned in 2-3 days. If insurance does not cover the test, the cost to the patient is approximately $50 per lesion or a maximum of $150, according to Dr. Kim.
 

Use in clinical practice

In Dr. Kim’s clinical experience, the PLA can be considered for suspicious pigmented lesions on cosmetically sensitive areas and for suspicious lesions in areas difficult to biopsy or excise. For example, she discussed the case of a 72-year-old woman with a family history of melanoma, who presented to her clinic with a longstanding pigmented lesion on her right upper and lower eyelids that had previously been treated with laser. She had undergone multiple prior biopsies over 12 years, which caused mild to moderate atypical melanocytic proliferation. The PLA result was double negative for PRAME and LINC in her upper and lower eyelid, “which provided reassurance to the patient,” Dr. Kim said. The patient continues to be followed closely for any clinical changes.

Another patient, a 67-year-old woman, was referred to Dr. Kim from out of state for a teledermatology visit early in the COVID-19 pandemic. The patient had a lesion on her right calf that was hard, raised, and pink, did not resemble other lesions on her body, and had been present for a few weeks. “Her husband had recently passed away from brain cancer and she was very concerned about melanoma,” Dr. Kim recalled. “She lived alone, and the adult son was with her during the teledermatology call to assist. The patient asked about the PLA test, and given her difficulty going to a medical office at the time, we agreed to help her with this test.” The patient and her son arranged another teledermatology visit with Dr. Kim after receiving the kit in the mail from DermTech, and Dr. Kim coached them on how to properly administer the test. The results came back as PRAME negative and LINC positive. A biopsy with a local provider was recommended and the pathology results showed an inflamed seborrheic keratosis.

“This case exemplifies a false-positive result. We should be sure to make patients aware of this possibility,” Dr. Kim said.

Incorporating PLA into clinical practice requires certain workflow considerations, with paperwork to fill out in addition to performing the adhesive test, collection of insurance information, mailing the kit via FedEx, retrieving the results, and following up with the patient, said Dr. Kim. “For select borderline pigmented lesions, I discuss the rationale of the test with patients, the possibility of false-positive and false-negative results and the need to return for a biopsy when there is positive result. Clinical follow-up is recommended for negative results. There is also the possibility of charge to the patient if the test is not covered by their insurance.”
 

Skin biopsy still the gold standard

Despite the availability of the PLA as an assessment tool, Dr. Kim emphasized that skin biopsy remains the gold standard for diagnosing melanoma. “Future prospective randomized clinical trials are needed to examine the role of genetic expression profiling in staging and managing patients,” she said.

In 2019, she and her colleagues surveyed 42 pigmented lesion experts in the United States about why they ordered one of three molecular tests on the market or not and how results affected patient treatment. The proportion of clinicians who ordered the tests ranged from 21% to 29%. The top 2 reasons respondents chose for not ordering the PLA test specifically were: “Feel that further validation studies are necessary” (20%) and “do not feel it would be useful in my practice” (18%).

Results of a larger follow-up survey on usage patterns of PLA of both pigmented lesion experts and general clinicians on this topic are expected to be published shortly.

Dr. Kim reported having no disclosures related to her presentation.

BOSTON – Although skin biopsy remains the gold standard for diagnosing early-stage melanoma, advances in genetic expression profiling are helping dermatologists provide a nuanced approach to managing suspicious lesions.

One such test, the Pigmented Lesional Assay (PLA) uses adhesive patches applied to lesions of concern at the bedside to extract RNA from the stratum corneum to help determine the risk for melanoma.

At the annual meeting of the American Academy of Dermatology, Caroline C. Kim, MD, director of melanoma and pigmented lesion clinics at Newton Wellesley Dermatology, Wellesley Hills, Mass., and Tufts Medical Center, Boston, spoke about the PLA, which uses genetic expression profiling to measure the expression level of specific genes that are associated with melanoma: PRAME (preferentially expressed antigen in melanoma) and LINC00518 (LINC). There are four possible results of the test: Aberrant expression of both LINC and PRAME (high risk); aberrant expression of a single gene (moderate risk); aberrant expression of neither gene (low risk); or inconclusive.

Validation data have shown a sensitivity of 91% and a specificity of 69% for the PLA, with a 99% negative predictive value; so a lesion that tested negative by PLA has a less than 1% chance of being melanoma. In addition, a study published in 2020 found that the addition of TERT (telomerase reverse transcriptase) mutation analyses increased the sensitivity of the PLA to 97%.

While the high negative predictive value is helpful to consider in clinical scenarios to rule-out melanoma for borderline lesions, one must consider the positive predictive value as well and how this may impact clinical care, Dr. Kim said. In a study examining outcomes of 381 lesions, 51 were PLA positive (single or double) and were biopsied, of which 19 (37%) revealed a melanoma diagnosis. In a large U.S. registry study of 3,418 lesions, 324 lesions that were PLA double positive were biopsied, with 18.7% revealing a melanoma diagnosis.

“No test is perfect, and this applies to PLA, even if you get a double-positive or double-negative test result,” Dr. Kim said. “You want to make sure that patients are aware of false positives and negatives. However, PLA could be an additional piece of data to inform your decision to proceed with biopsy on select borderline suspicious pigmented lesions. More studies are needed to better understand the approach to single- and double-positive PLA results.”

The PLA kit contains adhesive patches and supplies and a FedEx envelope for return to DermTech, the test’s manufacturer, for processing. The patches can be applied to lesions at least 4 mm in diameter; multiple kits are recommended for those greater than 16 mm in diameter. The test is not validated for lesions located on mucous membranes, palms, soles, nails, or on ulcerated or bleeding lesions, nor for those that have been previously biopsied. It is also not validated for use in pediatric patients or in those with skin types IV or higher. Results are returned in 2-3 days. If insurance does not cover the test, the cost to the patient is approximately $50 per lesion or a maximum of $150, according to Dr. Kim.
 

Use in clinical practice

In Dr. Kim’s clinical experience, the PLA can be considered for suspicious pigmented lesions on cosmetically sensitive areas and for suspicious lesions in areas difficult to biopsy or excise. For example, she discussed the case of a 72-year-old woman with a family history of melanoma, who presented to her clinic with a longstanding pigmented lesion on her right upper and lower eyelids that had previously been treated with laser. She had undergone multiple prior biopsies over 12 years, which caused mild to moderate atypical melanocytic proliferation. The PLA result was double negative for PRAME and LINC in her upper and lower eyelid, “which provided reassurance to the patient,” Dr. Kim said. The patient continues to be followed closely for any clinical changes.

Another patient, a 67-year-old woman, was referred to Dr. Kim from out of state for a teledermatology visit early in the COVID-19 pandemic. The patient had a lesion on her right calf that was hard, raised, and pink, did not resemble other lesions on her body, and had been present for a few weeks. “Her husband had recently passed away from brain cancer and she was very concerned about melanoma,” Dr. Kim recalled. “She lived alone, and the adult son was with her during the teledermatology call to assist. The patient asked about the PLA test, and given her difficulty going to a medical office at the time, we agreed to help her with this test.” The patient and her son arranged another teledermatology visit with Dr. Kim after receiving the kit in the mail from DermTech, and Dr. Kim coached them on how to properly administer the test. The results came back as PRAME negative and LINC positive. A biopsy with a local provider was recommended and the pathology results showed an inflamed seborrheic keratosis.

“This case exemplifies a false-positive result. We should be sure to make patients aware of this possibility,” Dr. Kim said.

Incorporating PLA into clinical practice requires certain workflow considerations, with paperwork to fill out in addition to performing the adhesive test, collection of insurance information, mailing the kit via FedEx, retrieving the results, and following up with the patient, said Dr. Kim. “For select borderline pigmented lesions, I discuss the rationale of the test with patients, the possibility of false-positive and false-negative results and the need to return for a biopsy when there is positive result. Clinical follow-up is recommended for negative results. There is also the possibility of charge to the patient if the test is not covered by their insurance.”
 

Skin biopsy still the gold standard

Despite the availability of the PLA as an assessment tool, Dr. Kim emphasized that skin biopsy remains the gold standard for diagnosing melanoma. “Future prospective randomized clinical trials are needed to examine the role of genetic expression profiling in staging and managing patients,” she said.

In 2019, she and her colleagues surveyed 42 pigmented lesion experts in the United States about why they ordered one of three molecular tests on the market or not and how results affected patient treatment. The proportion of clinicians who ordered the tests ranged from 21% to 29%. The top 2 reasons respondents chose for not ordering the PLA test specifically were: “Feel that further validation studies are necessary” (20%) and “do not feel it would be useful in my practice” (18%).

Results of a larger follow-up survey on usage patterns of PLA of both pigmented lesion experts and general clinicians on this topic are expected to be published shortly.

Dr. Kim reported having no disclosures related to her presentation.

BOSTON – Although skin biopsy remains the gold standard for diagnosing early-stage melanoma, advances in genetic expression profiling are helping dermatologists provide a nuanced approach to managing suspicious lesions.

One such test, the Pigmented Lesional Assay (PLA) uses adhesive patches applied to lesions of concern at the bedside to extract RNA from the stratum corneum to help determine the risk for melanoma.

At the annual meeting of the American Academy of Dermatology, Caroline C. Kim, MD, director of melanoma and pigmented lesion clinics at Newton Wellesley Dermatology, Wellesley Hills, Mass., and Tufts Medical Center, Boston, spoke about the PLA, which uses genetic expression profiling to measure the expression level of specific genes that are associated with melanoma: PRAME (preferentially expressed antigen in melanoma) and LINC00518 (LINC). There are four possible results of the test: Aberrant expression of both LINC and PRAME (high risk); aberrant expression of a single gene (moderate risk); aberrant expression of neither gene (low risk); or inconclusive.

Validation data have shown a sensitivity of 91% and a specificity of 69% for the PLA, with a 99% negative predictive value; so a lesion that tested negative by PLA has a less than 1% chance of being melanoma. In addition, a study published in 2020 found that the addition of TERT (telomerase reverse transcriptase) mutation analyses increased the sensitivity of the PLA to 97%.

While the high negative predictive value is helpful to consider in clinical scenarios to rule-out melanoma for borderline lesions, one must consider the positive predictive value as well and how this may impact clinical care, Dr. Kim said. In a study examining outcomes of 381 lesions, 51 were PLA positive (single or double) and were biopsied, of which 19 (37%) revealed a melanoma diagnosis. In a large U.S. registry study of 3,418 lesions, 324 lesions that were PLA double positive were biopsied, with 18.7% revealing a melanoma diagnosis.

“No test is perfect, and this applies to PLA, even if you get a double-positive or double-negative test result,” Dr. Kim said. “You want to make sure that patients are aware of false positives and negatives. However, PLA could be an additional piece of data to inform your decision to proceed with biopsy on select borderline suspicious pigmented lesions. More studies are needed to better understand the approach to single- and double-positive PLA results.”

The PLA kit contains adhesive patches and supplies and a FedEx envelope for return to DermTech, the test’s manufacturer, for processing. The patches can be applied to lesions at least 4 mm in diameter; multiple kits are recommended for those greater than 16 mm in diameter. The test is not validated for lesions located on mucous membranes, palms, soles, nails, or on ulcerated or bleeding lesions, nor for those that have been previously biopsied. It is also not validated for use in pediatric patients or in those with skin types IV or higher. Results are returned in 2-3 days. If insurance does not cover the test, the cost to the patient is approximately $50 per lesion or a maximum of $150, according to Dr. Kim.
 

Use in clinical practice

In Dr. Kim’s clinical experience, the PLA can be considered for suspicious pigmented lesions on cosmetically sensitive areas and for suspicious lesions in areas difficult to biopsy or excise. For example, she discussed the case of a 72-year-old woman with a family history of melanoma, who presented to her clinic with a longstanding pigmented lesion on her right upper and lower eyelids that had previously been treated with laser. She had undergone multiple prior biopsies over 12 years, which caused mild to moderate atypical melanocytic proliferation. The PLA result was double negative for PRAME and LINC in her upper and lower eyelid, “which provided reassurance to the patient,” Dr. Kim said. The patient continues to be followed closely for any clinical changes.

Another patient, a 67-year-old woman, was referred to Dr. Kim from out of state for a teledermatology visit early in the COVID-19 pandemic. The patient had a lesion on her right calf that was hard, raised, and pink, did not resemble other lesions on her body, and had been present for a few weeks. “Her husband had recently passed away from brain cancer and she was very concerned about melanoma,” Dr. Kim recalled. “She lived alone, and the adult son was with her during the teledermatology call to assist. The patient asked about the PLA test, and given her difficulty going to a medical office at the time, we agreed to help her with this test.” The patient and her son arranged another teledermatology visit with Dr. Kim after receiving the kit in the mail from DermTech, and Dr. Kim coached them on how to properly administer the test. The results came back as PRAME negative and LINC positive. A biopsy with a local provider was recommended and the pathology results showed an inflamed seborrheic keratosis.

“This case exemplifies a false-positive result. We should be sure to make patients aware of this possibility,” Dr. Kim said.

Incorporating PLA into clinical practice requires certain workflow considerations, with paperwork to fill out in addition to performing the adhesive test, collection of insurance information, mailing the kit via FedEx, retrieving the results, and following up with the patient, said Dr. Kim. “For select borderline pigmented lesions, I discuss the rationale of the test with patients, the possibility of false-positive and false-negative results and the need to return for a biopsy when there is positive result. Clinical follow-up is recommended for negative results. There is also the possibility of charge to the patient if the test is not covered by their insurance.”
 

Skin biopsy still the gold standard

Despite the availability of the PLA as an assessment tool, Dr. Kim emphasized that skin biopsy remains the gold standard for diagnosing melanoma. “Future prospective randomized clinical trials are needed to examine the role of genetic expression profiling in staging and managing patients,” she said.

In 2019, she and her colleagues surveyed 42 pigmented lesion experts in the United States about why they ordered one of three molecular tests on the market or not and how results affected patient treatment. The proportion of clinicians who ordered the tests ranged from 21% to 29%. The top 2 reasons respondents chose for not ordering the PLA test specifically were: “Feel that further validation studies are necessary” (20%) and “do not feel it would be useful in my practice” (18%).

Results of a larger follow-up survey on usage patterns of PLA of both pigmented lesion experts and general clinicians on this topic are expected to be published shortly.

Dr. Kim reported having no disclosures related to her presentation.

BOSTON – Among dermatology residents and attending dermatologists, rates of diagnostic accuracy and appropriate biopsy recommendations were significantly lower for patients with skin of color, compared with White patients, new research shows.

“Our findings suggest diagnostic biases based on skin color exist in dermatology practice,” lead author Loren Krueger, MD, assistant professor in the department of dermatology, Emory University School of Medicine, Atlanta, said at the Annual Skin of Color Society Scientific Symposium. “A lower likelihood of biopsy of malignancy in darker skin types could contribute to disparities in cutaneous malignancies,” she added.

Dr. Loren Krueger

The findings underscore that “for skin of color patients, you’re more likely to have a benign neoplasm biopsied, you’re less likely to have a malignant neoplasm biopsied, and more often, your etiology may be missed,” Dr. Krueger said at the meeting.

Of note, while 45% of respondents were dermatology residents or fellows, 20.4% had 1-5 years of experience, and about 28% had 10 to more than 25 years of experience.

And while 75% of the dermatology residents, fellows, and attendings were White, there was no difference in the probability of correctly identifying the underlying etiology in dark or light skin types based on the provider’s self-identified race.

Importantly, the patterns in the study of diagnostic discrepancies are reflected in broader dermatologic outcomes. The 5-year melanoma survival rate is 74.1% among Black patients and 92.9% among White patients. Dr. Krueger referred to data showing that only 52.6% of Black patients have stage I melanoma at diagnosis, whereas among White patients, the rate is much higher, at 75.9%.

“We know skin malignancy can be more aggressive and late-stage in skin of color populations, leading to increased morbidity and later stage at initial diagnosis,” Dr. Krueger told this news organization. “We routinely attribute this to limited access to care and lack of awareness on skin malignancy. However, we have no evidence on how we, as dermatologists, may be playing a role.”

Furthermore, the decision to perform biopsy or not can affect the size and stage at diagnosis of a cutaneous malignancy, she noted.

Key changes needed to prevent the disparities – and their implications – should start at the training level, she emphasized. “I would love to see increased photo representation in training materials – this is a great place to start,” Dr. Krueger said.

In addition, “encouraging medical students, residents, and dermatologists to learn from skin of color experts is vital,” she said. “We should also provide hands-on experience and training with diverse patient populations.”

The first step to addressing biases “is to acknowledge they exist,” Dr. Krueger added. “I am hopeful this inspires others to continue to investigate these biases, as well as how we can eliminate them.”

The study was funded by the Rudin Resident Research Award. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

BOSTON – Among dermatology residents and attending dermatologists, rates of diagnostic accuracy and appropriate biopsy recommendations were significantly lower for patients with skin of color, compared with White patients, new research shows.

“Our findings suggest diagnostic biases based on skin color exist in dermatology practice,” lead author Loren Krueger, MD, assistant professor in the department of dermatology, Emory University School of Medicine, Atlanta, said at the Annual Skin of Color Society Scientific Symposium. “A lower likelihood of biopsy of malignancy in darker skin types could contribute to disparities in cutaneous malignancies,” she added.

Dr. Loren Krueger

The findings underscore that “for skin of color patients, you’re more likely to have a benign neoplasm biopsied, you’re less likely to have a malignant neoplasm biopsied, and more often, your etiology may be missed,” Dr. Krueger said at the meeting.

Of note, while 45% of respondents were dermatology residents or fellows, 20.4% had 1-5 years of experience, and about 28% had 10 to more than 25 years of experience.

And while 75% of the dermatology residents, fellows, and attendings were White, there was no difference in the probability of correctly identifying the underlying etiology in dark or light skin types based on the provider’s self-identified race.

Importantly, the patterns in the study of diagnostic discrepancies are reflected in broader dermatologic outcomes. The 5-year melanoma survival rate is 74.1% among Black patients and 92.9% among White patients. Dr. Krueger referred to data showing that only 52.6% of Black patients have stage I melanoma at diagnosis, whereas among White patients, the rate is much higher, at 75.9%.

“We know skin malignancy can be more aggressive and late-stage in skin of color populations, leading to increased morbidity and later stage at initial diagnosis,” Dr. Krueger told this news organization. “We routinely attribute this to limited access to care and lack of awareness on skin malignancy. However, we have no evidence on how we, as dermatologists, may be playing a role.”

Furthermore, the decision to perform biopsy or not can affect the size and stage at diagnosis of a cutaneous malignancy, she noted.

Key changes needed to prevent the disparities – and their implications – should start at the training level, she emphasized. “I would love to see increased photo representation in training materials – this is a great place to start,” Dr. Krueger said.

In addition, “encouraging medical students, residents, and dermatologists to learn from skin of color experts is vital,” she said. “We should also provide hands-on experience and training with diverse patient populations.”

The first step to addressing biases “is to acknowledge they exist,” Dr. Krueger added. “I am hopeful this inspires others to continue to investigate these biases, as well as how we can eliminate them.”

The study was funded by the Rudin Resident Research Award. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

BOSTON – Among dermatology residents and attending dermatologists, rates of diagnostic accuracy and appropriate biopsy recommendations were significantly lower for patients with skin of color, compared with White patients, new research shows.

“Our findings suggest diagnostic biases based on skin color exist in dermatology practice,” lead author Loren Krueger, MD, assistant professor in the department of dermatology, Emory University School of Medicine, Atlanta, said at the Annual Skin of Color Society Scientific Symposium. “A lower likelihood of biopsy of malignancy in darker skin types could contribute to disparities in cutaneous malignancies,” she added.

Dr. Loren Krueger

The findings underscore that “for skin of color patients, you’re more likely to have a benign neoplasm biopsied, you’re less likely to have a malignant neoplasm biopsied, and more often, your etiology may be missed,” Dr. Krueger said at the meeting.

Of note, while 45% of respondents were dermatology residents or fellows, 20.4% had 1-5 years of experience, and about 28% had 10 to more than 25 years of experience.

And while 75% of the dermatology residents, fellows, and attendings were White, there was no difference in the probability of correctly identifying the underlying etiology in dark or light skin types based on the provider’s self-identified race.

Importantly, the patterns in the study of diagnostic discrepancies are reflected in broader dermatologic outcomes. The 5-year melanoma survival rate is 74.1% among Black patients and 92.9% among White patients. Dr. Krueger referred to data showing that only 52.6% of Black patients have stage I melanoma at diagnosis, whereas among White patients, the rate is much higher, at 75.9%.

“We know skin malignancy can be more aggressive and late-stage in skin of color populations, leading to increased morbidity and later stage at initial diagnosis,” Dr. Krueger told this news organization. “We routinely attribute this to limited access to care and lack of awareness on skin malignancy. However, we have no evidence on how we, as dermatologists, may be playing a role.”

Furthermore, the decision to perform biopsy or not can affect the size and stage at diagnosis of a cutaneous malignancy, she noted.

Key changes needed to prevent the disparities – and their implications – should start at the training level, she emphasized. “I would love to see increased photo representation in training materials – this is a great place to start,” Dr. Krueger said.

In addition, “encouraging medical students, residents, and dermatologists to learn from skin of color experts is vital,” she said. “We should also provide hands-on experience and training with diverse patient populations.”

The first step to addressing biases “is to acknowledge they exist,” Dr. Krueger added. “I am hopeful this inspires others to continue to investigate these biases, as well as how we can eliminate them.”

The study was funded by the Rudin Resident Research Award. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.